Category: Oncotarget

Defining the Complexity of EGFR Endocytosis in Cancer

April 27, 2023

In a new editorial perspective, researchers delve into the complex mechanisms underlying EGFR endocytosis and its potential as a therapeutic target.

Figure 1: SNX3 protein downregulation in breast tumors.

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EGFR (epidermal growth factor receptor) is a crucial protein that plays a significant role in various biological processes such as cell growth, proliferation, differentiation, and survival. Dysregulation of EGFR signaling has been implicated in the development and progression of numerous human cancers, including lung, breast and colon cancer. Therefore, EGFR has emerged as an attractive target for cancer therapy, and several drugs that target EGFR are in clinical use or under investigation.

In recent years, endocytosis, the process by which cells internalize molecules and transport them into intracellular compartments, has emerged as a critical modulator of EGFR signaling. Endocytosis of EGFR not only regulates the duration and intensity of EGFR signaling but also modulates the signaling output. Dysregulation of EGFR endocytosis has been implicated in the development of drug resistance to EGFR-targeted therapies, highlighting the importance of understanding the mechanisms that regulate EGFR endocytosis.

In a new editorial perspective, researchers Aysegul Sapmaz and Ayse Elif Erson-Bensan from Middle East Technical University provide an overview of the recent advances in our understanding of EGFR endocytosis and its role in EGFR signaling and cancer. The authors highlight the importance of the dynamic interplay between EGFR endocytosis and downstream signaling pathways and discuss how aberrant EGFR endocytosis contributes to drug resistance to EGFR-targeted therapies. On April 10, 2023, their editorial perspective was published in Oncotarget’s Volume 14, entitled, “EGFR endocytosis: more than meets the eye.”

“Here we review the role of the EGF-SNX3-EGFR axis in breast cancers with an extended discussion on deregulated EGFR endocytosis in cancer.”

EGFR Endocytosis

In a recent 2022 study, Sapmaz, Erson-Bensan and their team made significant contributions to understanding the role of deregulated endocytosis in cancer by describing the tumor suppressor role of Sorting Nexin 3 (SNX3) in triple-negative breast cancers (TNBCs). SNX3 is a protein-coding gene belonging to a family of proteins called sorting nexins, which are involved in sorting and trafficking of cellular membrane proteins and lipids. At the conclusion of their study, the researchers found that SNX3 is a critical player in TNBCs through the EGF-SNX3-EGFR axis.

“SNX3, an endosomal trafficking protein, is an emerging tumor suppressor in breast cancers as a target of the EGFactivated EGFR pathways and a modulator of EGFR protein levels.”

In the current editorial perspective by Sapmaz and Erson-Bensan, they discuss overexpression of EGFR and its activating mutations linked to various cancer phenotypes, including stemness, metastasis and drug resistance. Endocytosis and the internalization of EGFR play a crucial role in regulating its activity, which is dependent on post-translational modifications and regulated by various proteins, including ubiquitin. Deregulation of these players in endocytic processes has significant implications for EGFR activity in cancers. The ubiquitination status of EGFR and other proteins in the endocytic pathway is functionally essential and is balanced by E3 ubiquitin ligases and deubiquitinating enzymes (DUBs). Targeting these enzymes to alter ubiquitination dynamics could offer future perspectives in manipulating EGFR endocytosis and signaling in cancers.

The researchers discuss the non-canonical functions of endocytosis and endocytosis-related proteins, such as their involvement in nucleocytoplasmic shuttling and transcriptional activity. Several endocytic proteins have been found to interact with nuclear proteins and modulate gene transcription. Examples include EPS15, EPN1 and RNF11, which can shuttle between the cytoplasm and nucleus and have been shown to positively regulate transcription. Other endocytic proteins and adaptors have also been found to shuttle between the cytoplasm and nucleus with functions in endocytosis and gene expression. The authors emphasize the need for a better understanding of both the canonical and non-canonical functions of endocytic processes for normal physiology and diseases, including cancer and other pathologies.

“A better understanding of these backstage mechanisms will allow a more comprehensive understanding of receptor fate and activity.”

Conclusions

In conclusion, EGFR and its regulation through endocytosis have emerged as critical players in cancer development and progression. Dysregulation of EGFR endocytosis has been implicated in drug resistance to EGFR-targeted therapies, highlighting the importance of understanding the mechanisms that regulate this process. Recent advances in our understanding of EGFR endocytosis and its role in cancer have revealed the critical interplay between EGFR signaling and downstream pathways. The research by Sapmaz and Erson-Bensan sheds light on the tumor suppressor role of SNX3 in TNBCs and highlights the need for a better understanding of the canonical and non-canonical functions of endocytic processes in normal physiology and diseases, including cancer. Future research focusing on manipulating EGFR endocytosis and signaling could offer new perspectives on cancer therapy.

“Finally, before we can consider key endocytosis regulators as therapeutic targets, these candidate proteins must also be evaluated within the context of potential feedback mechanisms to modulate the biosynthesis and repopulation of receptors in cancer cells.”

Click here to read the full editorial perspective in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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The Evolution of Metastatic Cancer: Mechanisms and Drivers

April 14, 2023

In a new editorial, researchers explore genomic evolution in metastatic cancer, how therapy can drive it and the implications for developing new treatments.

The Evolution of Metastatic Cancer: Mechanisms and Drivers

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There are several theories that attempt to explain the genesis of cancer. One prominent theory is the genetic theory—proposing that cancer may arise from the accumulation of genetic mutations that alter the normal functioning of cells. These mutations can drive the formation of tumors, which can then spread to other parts of the body in a process known as metastasis. Metastatic cancer is often difficult to treat because it has evolved to become resistant to standard therapies.

“It is generally accepted that development of cancer is a slow process, likely spanning decades during which the developing neoplastic cells sequentially acquire genomic alterations that will eventually give rise to the primary tumor [1].”

In a new editorial, researchers Ditte S. Christensen and Nicolai J. Birkbak from Aarhus University discuss mechanisms of genomic evolution in metastatic cancer, how therapy can drive it and the implications for developing new treatments. Their editorial paper was published in Oncotarget on March 21, 2023, entitled, “Therapy drives genomic evolution in metastatic cancer.”

Therapy Can Drive Metastatic Cancer

Cancer cells are master adaptors and have a remarkable ability to evolve, especially in response to therapy. When cancer cells are exposed to chemotherapy, radiation or targeted therapies, they can develop resistance to these treatments by acquiring new genetic mutations. This can occur through a variety of mechanisms, including mutations in the genes that regulate cell division and DNA repair, as well as the acquisition of new genes that confer resistance to specific drugs.

In this editorial, the authors discuss how this process of genomic evolution can lead to the development of metastatic cancer. As cancer cells acquire new mutations that allow them to survive and grow in the presence of therapy, they may also acquire mutations that allow them to invade and colonize new tissues. This can lead to the development of new tumors in distant parts of the body, which are often more difficult to treat than the original tumor.

“How the ability to perform these multiple independent steps is acquired by cancer cells remains a mystery.”

Mechanisms of Metastatic Cancer

Understanding the mechanisms by which cancer cells evolve in response to therapy is essential for developing new treatments for metastatic cancer. The clonal bottleneck hypothesis and the gatekeeper mutation hypothesis are two different hypotheses that attempt to explain how cancer cells acquire the ability to metastasize and spread to distant parts of the body. The clonal bottleneck hypothesis proposes that metastatic cancer is the result of a single subclone of cancer cells from the primary tumor that successfully seeds new sites. According to this hypothesis, the cancer cells undergo a clonal bottleneck event where only a small number of cells from the primary tumor are able to survive and successfully colonize new tissues. This hypothesis suggests that the ability to metastasize is an inherent property of the subclone that successfully colonizes new sites.

On the other hand, the gatekeeper mutation hypothesis proposes that metastatic cancer is the result of a specific genetic mutation or mutations that act as gatekeepers, allowing cancer cells to metastasize and spread to new sites. According to this hypothesis, the ability to metastasize is acquired through the acquisition of one or more specific genetic mutations that allow cancer cells to bypass the normal checks and balances that prevent uncontrolled growth and invasion of surrounding tissues.

Exploring Gatekeeper Genomic Events

In a 2022 study, the authors of this editorial and their team explored the concept of gatekeeper genomic events by comparing primary and metastatic tumors on a large scale. Their large-scale analysis of more than 40,000 individual tumors from the AACR Genomics Evidence Neoplasia Information Exchange (GENIE) project found an increase in mutation burden and chromosomal instability in metastatic tumors, but no evidence of individual mutations driving the metastatic process itself. The concept of gatekeeper mutations remains a hypothesis, and further research is needed to explore this idea in more detail.

This study and others suggest that metastatic cancer dissemination involves a bottleneck event where a highly fit clone from a primary tumor successfully seeds distant sites. Strong selective pressure from anti-cancer therapy drives the acquisition of private driver mutations associated with therapy resistance in individual metastatic tumors. There is limited evidence for the existence of specific gatekeeper mutations. It is also possible that the primary driver of metastatic cancer is found outside the cancer cells.

“Indeed, it may be that a primary driver of metastatic cancer is to be found outside the cancer cells themselves, potentially through inflammation in the tumor-immune microenvironment or through interaction with a declining host immune system which may enable immune escape and sudden systemic dissemination by a highly proliferative primary tumor clone.”

Conclusions

In conclusion, the genetic theory of cancer proposes that cancer arises from genetic mutations that alter the normal functioning of cells, leading to the formation of tumors and metastasis. This editorial by Christensen and Birkbak highlights the process of genomic evolution in metastatic cancer and its implications for cancer treatment. Understanding the mechanisms by which cancer cells evolve in response to therapy is crucial for developing new treatments for metastatic cancer. Recent studies have shed light on the clonal origin of metastatic tumors and the role of selective pressure from anti-cancer therapy in the acquisition of private driver mutations associated with therapy resistance. While the concept of gatekeeper mutations remains a hypothesis, it is clear that the acquisition of aggressive cancer traits is the primary driver of metastatic potential. Further research is needed to explore this idea in more detail and develop effective therapies for metastatic cancer.

“It will be exciting to further explore these questions as more data becomes available on metastatic cancers, particularly with paired primary and metastatic tumor samples with sequential biopsies to facilitate the analysis of dynamic tumor evolution over time, rather than through static snapshots provided by samples obtained at a single time point.”

Click here to read the full editorial published in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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Targeting Pre-Leukemic Cells: New Hope for Preventing Childhood B-ALL

March 31, 2023

Researchers from Universidad Autónoma de Madrid published a new editorial in Oncotarget detailing a proof-of-principle experiment to prevent B-cell acute lymphoblastic leukemia (B-ALL).

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Childhood leukemia is a devastating disease that affects thousands of children every year. Despite significant advancements in the field of pediatric oncology, childhood leukemia remains a major cause of morbidity and mortality in children, with B-cell acute lymphoblastic leukemia (B-ALL) being the most common form.

Some cases of childhood B-ALL arise from congenital mutations that lead to a silent population of pre-leukemic cells. These cells at some point are triggered by a catalyst (possibly by delayed exposure to a common infection), acquire additional genetic mutations and ultimately develop into B-ALL. However, researchers have yet to fully understand how to target these pre-leukemic cells to prevent B-ALL.

In a new editorial paper, researchers César Cobaleda, Manuel Ramírez-Orellana, Carolina Vicente-Dueñas, Andreas Weiss, Kim E. Nichols, and Isidro Sánchez-García from Universidad Autónoma de Madrid discuss a novel method of targeting pre-leukemic cells in practice. On March 11, 2023, the team published their editorial in Oncotarget, entitled, “Proof-of-principle: targeted childhood leukemia prevention.”

“[…] one would have to find a way to specifically target these preleukemic cells. Recently, a mouse model recapitulating the phenotype of a leukemia-predisposition syndrome has allowed us to carry out a proof-of-principle experiment to achieve this very goal.”

The Study

Pax5 is a protein that plays a critical role in the development of white blood cells that produce antibodies to fight infections, B cells. A Pax5 mutation or deficiency can lead to a disruption in the development of B cells and compromise the immune system’s ability to fight off infections. Pax5+/- refers to an individual or organism that has one functional copy of the Pax5 gene and one non-functional copy. This condition is also known as heterozygosity.

“Children carrying heterozygous mutations affecting the B-cell master regulator gene PAX5 are predisposed to develop B-ALL; similarly, 25% of heterozygous Pax5+/− mice develop leukemia, but only after experiencing an immune stress, such as exposure to infection [2–4].”

In their recent study, the researchers used Pax5+/− mice (a mouse model carrying a leukemia-predisposition syndrome) to evaluate whether in vivo treatment with ruxolitinib, a Jak1/2 inhibitor, administered early in life is capable of killing pre-leukemic cells and preventing the development of acute leukemia. They found that treatment with ruxolitinib led to the disappearance of B-cell progenitors in Pax5+/-, but not in wild-type (WT), mice. When both experimental Pax5+/- and control WT animals were fed with ruxolitinib-containing chow for 14 or 28 days and then exposed to common mouse pathogens, the animals treated with ruxolitinib for 28 days showed a significant 90% reduction in the incidence of B-ALL compared to untreated mice or animals treated only for 14 days.

Ultra-deep sequencing studies of Pax5+/- mice showed that ruxolitinib acts by eliminating predisposed preleukemic B cells before the second “hit” (or catalyst) that leads to their descent into B-ALL. These findings suggest that an analogous approach could be used to prevent the development of B-ALL in children who carry germline mutations that predispose them to this disease.

“It is becoming increasingly clear that the existence of latent pretumoral cells is common to many types of both hematologic and solid cancers [7]; therefore, the concept described here could be considered a proof-of-principle strategy for the development of similar prophylactic approaches to prevent the progression of other malignancies.”

Figure 1: Targeted prevention of progression to B-ALL.

Summary & Conclusion

Childhood leukemia, specifically B-cell acute lymphoblastic leukemia, remains a significant cause of morbidity and mortality in children, despite advancements in pediatric oncology. The pre-leukemic cells that predispose children to B-ALL are not fully understood, making it challenging to prevent the disease. However, the recent study by Cobaleda C, et al. offers new hope. The proof-of-principle experiment demonstrates that early treatment with ruxolitinib can eliminate pre-leukemic cells and significantly reduce the incidence of B-ALL in the Pax5+/- mouse model.

Their findings suggest that a similar approach could be used to prevent B-ALL in children with germline mutations that predispose them to this disease. The concept described in this study could also serve as a strategy for developing prophylactic approaches to prevent the progression of other malignancies that share the existence of latent pretumoral cells. While further research is necessary, this study offers new possibilities in preventing childhood leukemia and improving the outcomes for children at risk.

“Still, some aspects remain unclear. For example, why do the majority of genetically predisposed animals (and most genetically predisposed children) not develop leukemia and stay healthy? In addition, what are the mechanisms by which environmental factors such as infection promote the acquisition of secondary mutations leading to malignant progression of preleukemic cells? These and other important questions still need to be answered if we are to fully understand and avert the appearance of B-ALL.”

Click here to read the full editorial published in Oncotarget.

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Unconventional Protein Secretion (UPS) in Cancer

March 16, 2023

Researchers from The Jikei University School of Medicine published a recent editorial perspective in Oncotarget, entitled, “Leakage? or Secretion? unconventional protein secretion in cancer.”

unconventional protein secretion in cancer — 3D rendering of structure/anatomy of human cell with organelles, nucleus, membrane, mitochondria, Golgi apparatus

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Conventional protein secretion is fairly well understood in this day and age. Proteins that are secreted through the classical, secretory vesicle-related pathway contain a signal peptide that guides them to the endoplasmic reticulum (ER), where they are further processed and transported to the Golgi apparatus. From there, the Golgi apparatus modifies, sorts and packages proteins for transport to their final destinations within the cell or for secretion outside of the cell.

However, in recent years, it has become clear that not all secreted proteins follow this conventional pathway. Instead, some proteins are secreted through unconventional pathways that do not require a signal peptide or the involvement of the ER or Golgi apparatus. In a recent editorial perspective published in Oncotarget on February 20, 2023, “Leakage? or Secretion? unconventional protein secretion in cancer,” researchers Kohji Yamada and Kiyotsugu Yoshida from The Jikei University School of Medicine in Tokyo, Japan, discuss unconventional protein secretion (UPS) and its significance in the progression of cancer.

“In contrast, the secretion of proteins that do not code for signal peptides may occur via two or more mechanisms, often collectively referred to as unconventional protein secretion (UPS).”

UPS in Cancer

The mechanism of action of UPS in cancer cells is still unclear, however, UPS may be carried out through multiple mechanisms. One such mechanism is the lysosome-mediated secretion pathway, in which proteins are secreted through lysosome organelles that break down and recycle cellular waste. Another mechanism is the exosome-mediated secretion pathway, in which proteins are packaged into small vesicles called exosomes and released from the cell.

In their editorial perspective, Yamada and Yoshida focus on the unconventional secretion of proteins in cancer cells. They note that these unconventional pathways have been implicated in the progression of various types of cancer, especially in liver cancers. The authors quickly began to discuss the question in the title of their paper: leakage or secretion? Since cancer cells are often surviving in harsh external environments, they tend to undergo damage to their cellular membranes. This makes it difficult to identify whether the proteins found in the extracellular environment have been leaked or secreted from the cell.

“Particularly, in liver cancer, cytosolic proteins are secreted actively, but not just leaked. In our experiments with liver cancer cell lines, we demonstrated that proliferating cells under normal culture conditions release importin α1 and PKCδ [2, 3].”

The researchers then delve into the different proteins secreted through UPS and their role in cancer. They note that cancer cells often secrete proteins that promote tumor growth and metastasis through these unconventional pathways. For example, the lysosome-mediated secretion of the protein cathepsin B has been shown to promote cancer cell invasion and metastasis. Exosome-mediated secretion of various proteins, including growth factors and cytokines, has been linked to tumor growth and immune evasion.

Conclusion

Overall, the editorial perspective by Yamada and Yoshida provides valuable insight into the significance of unconventional protein secretion in cancer. While further research is needed in order to understand UPS, this editorial perspective highlights its potential as a therapeutic target. The authors emphasize the importance of continuing research into this area of cancer biology.

“In conclusion, we and other researchers have accumulated a series of evidences on UPS and its biological significance in cancer. However, the mechanism of action of UPS in cancer cells remains unclear. How cytosolic proteins localized to the ER via E-Syt1 migrate into vesicles for secretion or whether their secretory mechanisms involve other organelles, including the Golgi apparatus, autophagosomes, or lysosomes, remains unclear. In the future, if the route of UPS that is centered on E-Syt1 is elucidated, this will presumably lead to not only a basic understanding of liver cancer but also to the development of diagnostic and therapeutic strategies.”

Click here to read the full editorial perspective published in Oncotarget.

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The Role of Kras and Canonical Wnt Pathways in Biliary Tract Cancers

March 1, 2023

In a recent Oncotarget editorial, researchers discuss Kras and the canonical Wnt pathway in biliary tract cancers, and potential theraputic strategies using these targets.

Figure 1: The role of Kras and canonical Wnt pathways for tumorigenesis of extrahepatic biliary system.

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The extrahepatic biliary system is a network of tubes and ducts that carry bile from the liver to the small intestine, where it helps digest fats. Biliary tract cancers, including gallbladder cancer and cholangiocarcinoma, are rare but aggressive cancers that arise from this system. Understanding the molecular mechanisms that drive these cancers is crucial for developing effective therapies.

“Despite advances in diagnosis and therapy, 5-year survival rate of biliary cancer is only 5% to 15% [7, 8].”

In a new editorial, researchers Munemasa Nagao, Akihisa Fukuda and Hiroshi Seno from Kyoto University Graduate School of Medicine discuss the latest research on the role of Kras and the canonical Wnt pathway in the development of biliary tract cancers. On January 26, 2023, their paper was published in Oncotarget’s Volume 14, entitled, “The role of Kras and canonical Wnt pathways for tumorigenesis of extrahepatic biliary system.”

Kras and The Canonical Wnt Pathway in Biliary Tract Cancers

Kras is a gene that plays a key role in regulating cell growth and division. Mutations in Kras are common in many types of cancer, including biliary tract cancers. The authors of this editorial note that recent studies have shown that Kras mutations are relatively frequent in biliary cancers. These mutations activate the Kras protein, leading to uncontrolled cell growth and division.

The canonical Wnt pathway is another molecular pathway that has been implicated in cancer development. The Wnt pathway helps regulate cell growth and division during embryonic development and in adult tissues. Abnormal activation of the Wnt pathway has been linked to several types of cancer, including colon cancer and liver cancer. Recent studies have shown that the canonical Wnt pathway is also activated in biliary tract cancers.

“However, the role of the KRAS and WNT pathways in biliary tumorigenesis remained unclear.”

A protein called beta-catenin, which is a key component of the Wnt pathway, is often overexpressed in biliary tract cancers. This leads to the activation of downstream target genes that promote cell growth and division. The researchers also discussed results from their 2022 study investigating the role of the Kras and canonical Wnt pathways in the tumorigenesis of the extrahepatic biliary system using a genetically engineered mouse (GEM) model.

“In summary, concurrent activation of the Kras and Wnt pathways in the extrahepatic biliary system induced ICPN and BilIN, which can progress to biliary cancer (Figure 1). This study provides the first novel GEM that recapitulates human ICPN and BilIN, establishing them precancerous lesions. This work shows how dysregulation of canonical cell growth pathways drives precursors to biliary cancers and identifies several molecular vulnerabilities as potential therapeutic targets in these precursors to prevent oncogenic progression.”

Potential Therapeutic Strategies for Biliary Tract Cancers

The researchers go on to discuss the concurrent activation, or crosstalk, between Kras and these pathways in biliary tract cancers. They note that several studies have shown that Kras mutations can activate the Wnt pathway, leading to even more aggressive cancer growth. This suggests that targeting both pathways may be necessary for effective therapy.

Potential therapeutic strategies targeting Kras and Wnt pathways in biliary tract cancers were discussed in this editorial. Several drugs that target these pathways are currently in development, and some are already being tested in clinical trials. The authors suggest that combining these drugs with chemotherapy or other targeted therapies may be a promising approach for treating biliary tract cancers.

“To develop novel preventive and therapeutic approaches for extrahepatic biliary cancer, it is also important to clarify the role of other altered genes by using a GEM model and/or human samples.”

Conclusion

Overall, this editorial provides a comprehensive overview of the latest research on the molecular mechanisms underlying biliary tract cancers. Their discussion of the role of Kras and the canonical Wnt pathway highlights the importance of understanding these pathways for developing effective therapies. The potential for combination therapies targeting both Kras and the canonical Wnt pathway is particularly intriguing, and could offer new hope for patients with these aggressive cancers.

Withstanding, it is important to note that more research is needed before these ideas can be translated into clinical practice. The authors themselves acknowledge that the development of effective targeted therapies for biliary tract cancers is still in its early stages. However, with continued research and collaboration, it is possible that new treatments will emerge that can improve the prognosis for patients with these challenging cancers.

Click here to read the full editorial published in Oncotarget.

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Oncotarget’s Top 10 Papers in 2022 (Crossref Data)

February 22, 2023

Crossref is a non-profit organization that logs and updates citations for scientific publications. Each month, Crossref identifies a list of the most popular Oncotarget papers based on the number of times a DOI is successfully resolved.

Below are Crossref’s Top 10 Oncotarget DOIs in 2022.

Read Crossref’s Top 10 Oncotarget DOIs in 2022.

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#10: Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19 complications, and vaccine side effects

DOI: https://doi.org/10.18632/oncotarget.28088

Author: Yuri Lazebnik

Institution: Lerna Consulting

Quote: “A distinctive feature of the SARS-CoV-2 spike protein is its ability to efficiently fuse cells, thus producing syncytia found in COVID-19 patients. This commentary proposes how this ability enables spike to cause COVID-19 complications as well as side effects of COVID-19 vaccines, and suggests how these effects can be prevented.”

#9: A Jurkat 76 based triple parameter reporter system to evaluate TCR functions and adoptive T cell strategies

DOI: https://doi.org/10.18632/oncotarget.24807

Authors: Sandra Rosskopf, Judith Leitner, Wolfgang Paster, Laura T. Morton, Renate S. Hagedoorn, Peter Steinberger, and Mirjam H.M. Heemskerk

Institutions: Medical University of Vienna and Leiden University Medical Center

Quote: “Adoptive T cell therapy using TCR transgenic autologous T cells has shown great potential for the treatment of tumor patients. Thorough characterization of genetically reprogrammed T cells is necessary to optimize treatment success. Here, we describe the generation of triple parameter reporter T cells based on the Jurkat 76 T cell line for the evaluation of TCR and chimeric antigen receptor functions as well as adoptive T cell strategies.”

#8: IL-37 suppresses hepatocellular carcinoma growth by converting pSmad3 signaling from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/P21 tumor-suppressive signaling

DOI: https://doi.org/10.18632/oncotarget.13196

Authors: Rui Liu, Chengyong Tang, Ai Shen, Huating Luo, Xufu Wei, Daofeng Zheng, Chao Sun, Zhongtang Li, Di Zhu, Tingting Li, and Zhongjun Wu

Institution: The First Affiliated Hospital of Chongqing Medical University

Quote: “IL-37 has been characterized as a fundamental inhibitor of innate immunity and a tumor suppressor in several cancers. However, the molecular mechanism of IL-37 in hepatocellular carcinoma (HCC) is largely unclear. In this study we found IL-37 expression was down-regulated in human HCC tissues and cell lines, and was negatively correlated with tumor size, vascular invasion, as well as overall-survial and disease-free survival (OS and DFS) of HCC.”

#7: Apatinib-based targeted therapy against pulmonary sarcomatoid carcinoma: a case report and literature review

DOI: https://doi.org/10.18632/oncotarget.25989

Authors: Xiaofeng Li, Yueming He, Jinfeng Zhu, Hongxia Pang, Yongwei Lin, and Jinyang Zheng

Institution: Affiliated Quanzhou First Hospital of Fujian Medical University

Quote: “Sarcomatoid carcinoma is a rare malignancy characterized by a combination of epithelial and sarcoma or sarcoma-like components. In this study, we reported one case of pulmonary sarcomatoid carcinoma and evaluated the safety and efficacy of apatinib, a tyrosine kinase inhibitor selectively targeting vascular endothelial growth factor receptor 2, in treating this disease.”

#6: Treasures from trash in cancer research

DOI: https://doi.org/10.18632/oncotarget.28308

Authors: Fabiano Cordeiro Moreira, Dionison Pereira Sarquis, Jorge Estefano Santana de Souza, Daniel de Souza Avelar, Taíssa Maria Thomaz Araújo, André Salim Khayat, Sidney Emanuel Batista dos Santos, and Paulo Pimentel de Assumpção

Institutions: Universidade Federal do Pará and Universidade Federal do Rio Grande do Norte

Quote: “Cancer research has significantly improved in recent years, primarily due to next-generation sequencing (NGS) technology. Consequently, an enormous amount of genomic and transcriptomic data has been generated. In most cases, the data needed for research goals are used, and unwanted reads are discarded. However, these eliminated data contain relevant information. Aiming to test this hypothesis, genomic and transcriptomic data were acquired from public datasets.”

#5: Real-world survival analysis by tumor mutational burden in non-small cell lung cancer: a multisite U.S. study

DOI: https://doi.org/10.18632/oncotarget.28178

Authors: Connor Willis, Hillevi Bauer, Trang H. Au, Jyothi Menon, Sudhir Unni, Dao Tran, Zachary Rivers, Wallace Akerley, Matthew B. Schabath, Firas Badin, Ashley Sekhon, Malini Patel, Bing Xia, Beth Gustafson, John L. Villano, John-Michael Thomas, Solomon J. Lubinga, Michael A. Cantrell, Diana Brixner, and David Stenehjem

Institutions: University of Utah, University of Minnesota Duluth, Huntsman Cancer Institute, H. Lee Moffitt Cancer Center and Research Institute, Baptist Health Medical Group, MetroHealth Medical Center, Rutgers Cancer Institute of New Jersey, University of Southern California, Saint Luke’s Cancer Institute, University of Kentucky, and Bristol Myers Squibb

Quote: “Tumor mutational burden (TMB) is a potential biomarker to predict tumor response to immuno-oncology agents in patients with metastatic non-small cell lung cancer (NSCLC). A multi-site cohort study evaluated patients diagnosed with stage IV NSCLC between 2012 and 2019 who had received comprehensive genomic profiling (CGP) and any NSCLC-related treatment at 9 U.S. cancer centers. Baseline characteristics and clinical outcomes were compared between patients with TMB <10 and TMB ≥10.”

#4: Continuous treatment with abemaciclib leads to sustained and efficient inhibition of breast cancer cell proliferation

DOI: https://doi.org/10.18632/oncotarget.28249

Authors: Raquel Torres-Guzmán, Maria Patricia Ganado, Cecilia Mur, Carlos Marugan, Carmen Baquero, Yanzhu Yang, Yi Zeng, Huimin Bian, Jian Du, Alfonso de Dios, Oscar Puig, and María José Lallena

Institution: Eli Lilly and Company

Quote: “Abemaciclib is an oral, selective cyclin-dependent kinase 4 & 6 inhibitor (CDK4 & 6i), approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) as monotherapy for endocrine refractory disease, and with endocrine therapy (ET) for initial treatment and after progression on ET. Abemaciclib has also shown clinical activity in combination with ET in patients with high risk early BC (EBC). Here, we examined the preclinical attributes of abemaciclib and other CDK4 & 6i using biochemical and cell-based assays. In vitro, abemaciclib preferentially inhibited CDK4 kinase activity versus CDK6, resulting in inhibition of cell proliferation in a panel of BC cell lines with higher average potency than palbociclib or ribociclib.”

#3: Increased gut permeability in cancer cachexia: mechanisms and clinical relevance

DOI: https://doi.org/10.18632/oncotarget.24804

Authors: Laure B. Bindels, Audrey M. Neyrinck, Audrey Loumaye, Emilie Catry, Hannah Walgrave, Claire Cherbuy, Sophie Leclercq, Matthias Van Hul, Hubert Plovier, Barbara Pachikian, Luis G. Bermúdez-Humarán, Philippe Langella, Patrice D. Cani, Jean-Paul Thissen, and Nathalie M. Delzenne

Institutions: Université Catholique de Louvain and Université Paris-Saclay

Quote: “Intestinal disorders often occur in cancer patients, in association with body weight loss, and this alteration is commonly attributed to the chemotherapy. Here, using a mouse model of cancer cachexia induced by ectopic transplantation of C26 cancer cells, we discovered a profound alteration in the gut functions (gut permeability, epithelial turnover, gut immunity, microbial dysbiosis) independently of any chemotherapy.”

#2: Inflammatory responses and inflammation-associated diseases in organs

DOI: https://doi.org/10.18632/oncotarget.23208

Authors: Linlin Chen, Huidan Deng, Hengmin Cui, Jing Fang, Zhicai Zuo, Junliang Deng, Yinglun Li, Xun Wang, and Ling Zhao

Institution: Sichuan Agricultural University

Quote: “Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds. These factors may induce acute and/or chronic inflammatory responses in the heart, pancreas, liver, kidney, lung, brain, intestinal tract and reproductive system, potentially leading to tissue damage or disease. Both infectious and non-infectious agents and cell damage activate inflammatory cells and trigger inflammatory signaling pathways, most commonly the NF-κB, MAPK, and JAK-STAT pathways. Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.”

#1: Proteomic profiling of skeletal and cardiac muscle in cancer cachexia: alterations in sarcomeric and mitochondrial protein expression

DOI: https://doi.org/10.18632/oncotarget.25146

Authors: Angie M. Y. Shum, Anne Poljak, Nicholas L. Bentley, Nigel Turner, Timothy C. Tan, and Patsie Polly

Institutions: UNSW Sydney, Western Clinical School and Westmead Hospital

Quote: “Cancer cachexia is observed in more than 50% of advanced cancer patients, and impairs quality of life and prognosis. A variety of pathways are likely to be dysregulated. Hence, a broad-spectrum understanding of the disease process is best achieved by a discovery based approach such as proteomics.”

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Oncotarget

Controlling Glycolytic Flux: Therapy Challenges and Solutions

February 16, 2023

In a new editorial paper, researchers from the University of Oxford explore challenges and potential solutions for controlling glycolytic flux by blocking lactate transporters in disease therapies.

Targeting Lactate Transporters for Disease Therapies

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The process of glycolysis, or the conversion of glucose to energy in cells, is a critical component of many biological processes. This process is highly regulated, and glycolytic flux has been implicated in a variety of disease states, including cancer and diabetes. Despite significant advances in our understanding of glycolysis, researchers continue to find it difficult to control glycolytic flux.

“Overall, glycolysis facilitates tumour proliferation and survival, and has become a hotly-pursued target for therapeutic inhibition.”

In a new editorial paper, researchers Wiktoria Blaszczak and Pawel Swietach from the University of Oxford explored the challenges of this issue and potential solutions. On January 26, 2023, their editorial was published in Oncotarget and entitled, “Permeability and driving force: why is it difficult to control glycolytic flux by blocking lactate transporters?“

“In our recent study (Blaszczak et al. (2022)), using a panel of pancreatic ductal adenocarcinoma cell lines, we characterised how extracellular acidity feeds back to inhibit further glycolytic acid production [6].”

Blocking Lactate Transporters: Challenges

Lactate is produced as a byproduct of glycolysis. Lactate transporters are responsible for moving lactate out of cells. Blocking these transporters has long been thought of as a potential way to slow or stop glycolytic flux. However, as the authors of this editorial point out, attempts to do so have been met with limited success.

One of the key challenges in blocking lactate transporters is their complex regulation. These transporters are highly permeable to lactate, meaning that even small changes in their activity can have a significant impact on lactate flux. Additionally, lactate transporters are regulated by a variety of factors, including pH, ion concentrations and intracellular signaling pathways. This complexity makes it difficult to design drugs that selectively target lactate transporters without affecting other cellular processes.

Another challenge in blocking lactate transporters is the driving force that fuels lactate transport. The movement of lactate out of cells is driven by a concentration gradient, meaning that lactate moves from areas of high concentration to areas of low concentration. However, this gradient is often very small, meaning that even small changes in the activity of lactate transporters can have a significant impact on lactate flux. Additionally, lactate transporters are often coupled with other transporters, such as H+ transporters, which can further complicate efforts to block lactate transport.

Blocking Lactate Transporters: Solutions

Despite these challenges, the authors suggest that there may be ways to overcome them and better control glycolytic flux by targeting lactate transporters. One potential approach is to develop drugs that selectively target lactate transporters and are not affected by other cellular processes. This could be achieved by exploiting the structural differences between lactate transporters and other transporters. Additionally, targeting the intracellular signaling pathways that regulate lactate transporters could be a way to more selectively block lactate transport.

Another potential approach to controlling glycolytic flux is to target the driving force that fuels lactate transport. This could be achieved by altering the concentration gradient of lactate, either by blocking lactate production or by increasing lactate consumption. Additionally, targeting other transporters that are coupled with lactate transporters, such as H+ transporters, could be a way to indirectly control lactate transport and glycolytic flux.

“Overall, a decrease in permeability will increase driving force, thereby restoring flux.”

Conclusion

Overall, the researchers highlight the complex nature of lactate transport and the challenges that must be overcome to control glycolytic flux by blocking lactate transporters. Additionally, the authors suggest that there are potential solutions to these challenges and that continued research could lead to new insights into the regulation of glycolysis and the development of new therapies for diseases associated with alterations in glycolytic flux.

“Regardless of the chosen approach, it is likely that any successful therapeutic strategy for targeting glycolysis will be multifaceted to overcome some of the intricacies of complex pathways.”

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Oncotarget

The Importance of CD56 in the Fight Against Multiple Myeloma

February 2, 2023

In a new Oncotarget editorial, researchers discussed their study on CD56 in multiple myeloma.

Figure 1: Graphical representation of the main findings of the summarized paper.

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Multiple myeloma (MM) is a type of blood cancer that affects plasma cells in the bone marrow. These plasma cells, which are responsible for producing antibodies, become abnormal and begin to grow uncontrollably. This results in a buildup of abnormal cells in the bone marrow, leading to decreased production of healthy blood cells, bone damage and a host of other symptoms. MM is incredibly heterogenic, and this variability often leads to unsatisfactory long-term treatment outcomes in many patients with MM. Targets for new treatments and biomarkers of response are needed to improve patient outcomes.

In a new editorial paper published in Oncotarget, researchers Francesca Cottini and Don Benson from The Ohio State University discuss a 2022 research paper they co-authored in which CD56 (or neuronal cell adhesion molecule; NCAM1) was thoroughly described as a biomarker and therapeutic target in multiple myeloma. On January 26, 2023, their editorial about this research paper was published in Oncotarget, entitled, “To be or not to be: the role of CD56 in multiple myeloma.”

“Among others, CD56 is present at variable levels in approximately 70% of patients with multiple myeloma; however, very little is known about CD56 role in multiple myeloma.” (2022 Cottini et al.)

CD56 in MM

The role of CD56 in multiple myeloma is a topic of ongoing research and discussion among scientists and medical professionals. CD56 is a protein that is found on the surface of many different cell types, including plasma cells. Researchers have demonstrated that it plays a key role in the development and progression of multiple myeloma, making it a potential target for new treatments.

One of the main functions of CD56 is to regulate the growth and survival of plasma cells. In normal cells, CD56 helps to prevent uncontrolled growth and division of cells. However, in multiple myeloma cells, CD56 appears to play a different role. Research has shown that CD56 is overexpressed in multiple myeloma cells, leading to an increase in cell growth and division.

Additionally, CD56 has been found to play a role in the immune system’s response to cancer cells. In multiple myeloma, CD56 can suppress the immune system’s response to the abnormal cells, allowing them to continue growing unchecked. This is why multiple myeloma is often resistant to traditional cancer treatments such as chemotherapy and radiation.

Targeting CD56 in MM

There are currently several strategies being explored to target CD56 in multiple myeloma. One approach is to use drugs that block the function of CD56, in order to prevent it from promoting cell growth and division. Another approach is to use immunotherapies that stimulate the immune system to attack the abnormal cells. This can help to overcome the suppression of the immune system by CD56 and lead to more effective cancer treatment.

There is also research being conducted into the use of CAR T-cell therapy. CAR T-cell therapy involves genetically modifying a patient’s own immune cells to attack the cancer cells. In this type of therapy, the immune cells are modified to target CD56 specifically, which allows them to attack and destroy the multiple myeloma cells more effectively.

Cottini et al.

In this editorial, the researchers discuss their study, which looked at CD56-expressing clonal MM cells in more than 700 patients at the time of MM diagnosis. The researchers found that the size of these cells varied between patients and increased as the disease worsened. Results demonstrated that having a large amount of these cells was linked to worse outcomes and shorter responses to treatment.

The study then looked at how changing the expression of CD56 affected the behavior of MM cells and found that it influenced cell growth and survival. They also discovered that a protein called RSK2 and another called CREB1 play a role in this process. They then tested medicines to block these proteins and found that they were effective in killing MM cells that had a high amount of CD56, but not as much in those with low levels of CD56.

“The authors’ preclinical data support the use of synthetic lethal approaches by CREB1/RSK2 inhibition in combination with lenalidomide, as a strategy to overcome CRBN downregulation in CD56-high MM.”

Conclusion

“In summary, this study provides a detailed description of CD56 role in MM, opening new clinically relevant scenarios.”

The role of CD56 in multiple myeloma is complex and still not fully understood. However, the researchers who wrote this editorial aimed to clearly define CD56’s key role in the development and progression of this disease, making it a potential target for new treatments. By better understanding the function of CD56, scientists and medical professionals can continue to develop new and innovative therapies to improve the lives of those affected by multiple myeloma.

“Since the majority of clinical laboratories have the capability to perform CD56 staining and define a threshold of positivity, CD56 expression can be both a prognostic and predictive factor of response to therapies, an unmet need in the MM field (Figure 1).”

Click here to read the full editorial published in Oncotarget.

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Oncotarget

Researchers Identify New Drug Candidates to Treat DLST+ Tumors

January 19, 2023

The increased expression of DLST has recently been associated with increased tumor aggression and a poor prognosis in neuroblastoma and triple-negative breast cancer.

Figure 3: Analysis of DLST-activated cell lines revealed sensitivity to protein kinase inhibiting the ERK/MAPK pathway.

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Dihydrolipoamide S-succinyltransferase (DLST) is a crucial gene/protein/enzyme involved in the oxidative phosphorylation (OXPHOS) pathway and cellular energy production. Recent studies have demonstrated that, in neuroblastoma and triple-negative breast cancer (TNBC), increased expression of DLST is associated with increased tumor aggression and a poor disease prognosis. Researchers also found that, in leukemia and TNBC cell lines, the knockdown of DLST leads to apoptosis. These findings suggest that neuroblastoma and TNBC may benefit from DLST-inhibiting cancer therapy.

In light of this evidence, researchers Christina Kuhn, Myriam Boeschen, Manuel Philip, Torsten Schöneberg, Doreen Thor, and Susanne Horn from the University of Leipzig, University Duisburg-Essen and the German Cancer Consortium investigated approved drugs that may target DLST-activated tumors. In their recent study, the team used data from the Genomics of Drug Sensitivity in Cancer (GDSC) project to identify new drug candidates for the treatment of DLST-activated tumors. On January 12, 2023, their research paper was published in Oncotarget’s Volume 14, entitled, “Candidate drugs associated with sensitivity of cancer cell lines with DLST amplification or high mRNA levels.”

The Study

“With the advent of complex genetic datasets of roughly 1000 cell lines in the Cancer Cell Line Encyclopedia (CCLE) and on drug resistance in the Genomics of Drug Sensitivity in Cancer project (GDSC), analyses of drug sensitivity have become possible on a larger scale [6, 7].”

Since neuroblastoma and TNBC tumor cell viability may be DLST-dependent, DLST is a promising target for cancer therapy. The researchers used the Cancer Cell Line Encyclopedia (CCLE) to identify cancer cell lines with DLST amplifications or high mRNA levels. They then measured the sensitivity of these DLST+ cell lines to 250 drugs in the GDSC dataset and compared the data to a subset of cell lines without DLST amplifications or high mRNA levels.

“To identify drugs that inhibit viability of specifically DLST-activated tumor cells, we compared cell lines with supposedly activating changes of DLST (DNA amplification, high mRNA levels) to cell lines without DLST changes.”

Results & Conclusions

“DLST-altered cell lines were more sensitive to 7 approved drugs, among these obatoclax mesylate, a BCL2 inhibitor that reduces OXPHOS in human leukemia stem cells.”

The researchers identified seven drug candidates that demonstrated significantly higher sensitivity in DLST+ cell lines than in the control cell lines. In addition to a BCL2 inhibitor found to reduce OXPHOS, multiple protein kinase inhibitors were identified as efficient in the DLST+ cell lines. This suggests that DLST-altered cell lines may also be vulnerable to ERK/MAPK pathway-targeting drugs. The researchers propose that the drug candidates identified in this study warrant further drug efficacy testing in knock-in cell lines and DLST-activated tumors.

“We therefore conclude that, in addition to OXPHOS, protein kinases could be potential targets of therapy in the presence of DLST amplifications or high mRNA levels.”

Click here to read the full research paper published by Oncotarget.

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Oncotarget

Novel Antibody Drug Conjugate Improves Murine Acute Myeloid Leukemia

January 4, 2023

Researchers from Astellas Pharma Inc. investigated the efficacy of a novel antibody drug conjugate combined with venetoclax and azacitidine in a mouse model of acute myeloid leukemia.

Novel Antibody Drug Conjugate Improves Murine Acute Myeloid Leukemia

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The average age of patients with acute myeloid leukemia (AML) is 67 years old. Older adults generally have a lower tolerance for treatments that exhibit high off-target toxicity. Additionally, chemotherapy-relapsed or -refractory (R/R) AML patients are often at an advanced stage of disease and are therefore more likely to have comorbidities that may reduce their tolerance for harsh treatments.

Thus, pharmaceutical AML drugs with high efficacy and low toxicity are in high demand. Antibody drug conjugates (ADCs) are emerging as promising therapeutic approaches to more safely treat hematological malignancies by reducing side effects. ADCs are designed to decrease damage to healthy tissues by specifically targeting tumor-associated antigens attached to cancer cells.

“Antibody drug conjugates (ADC) are one of the modalities that aims to dissociate drug efficacy from toxicity. ADC consists of three components: antibody specific for tumor associated antigen, drug linker and cytotoxic payload.”

Astellas Pharma

Recently, researchers from Astellas Pharma Inc. (a pharmaceutical company in Japan) developed ASP1235—a novel ADC that targets Fms-like tyrosine kinase 3 (FLT3). In more than 90% of AML patients, FLT3 is overexpressed on leukemic blasts. ASP1235 is designed to target FLT3-positive leukemia cells and deliver the cytotoxic drug payload to these cells. However, this drug alone was found to have only a mild effect on AML cells, prompting researchers to assess the efficacy of ASP1235 in combination with other drugs.

In a new study, Astellas Pharma researchers Hirofumi Tsuzuki, Tatsuya Kawase, Taisuke Nakazawa, Masamichi Mori, and Taku Yoshida investigated the efficacy of ASP1235 combined with venetoclax (an anti-apoptotic agent) and azacitidine (a DNA methyltransferase inhibitor) in an experimental mouse model of AML. Their research paper was published in Oncotarget on December 20, 2022, and entitled, “Anti-tumor effect of antibody drug conjugate ASP1235 targeting Fms-like tyrosine kinase 3 with venetoclax plus azacitidine in an acute myeloid leukemia xenograft mouse model.”

“In this study, we sought to evaluate the therapeutic effect of ASP1235 in combination with venetoclax plus azacitidine, a novel standard-of-care treatment for elderly AML patients, in ASP1235 poor sensitive AML cells.”

The Study

The researchers first aimed to determine an AML cell line that was only partially sensitive to ASP1235 monotherapy. They determined the THP-1 cell line was appropriate for further investigation. They compared FLT3 and Bcl-2 expression levels in THP-1 cells with primary leukemic cells from chemotherapy R/R AML patients to consider the clinical relevance of each. In THP-1 cells, the expression levels of FLT3 and Bcl-2 were found to be clinically relevant.

“It has been reported that the proportion of patients showing high Bcl-2 expression was greater in chemotherapy R/R AML patients compared to that in newly diagnosed patients [4]. Thus, we investigated the expression levels of Bcl-2 together with FLT3 to further consider the relevance of THP-1 cells for evaluation on the combination treatment with venetoclax.”

To confirm their in vitro findings, they used a THP-1 xenograft mouse model for in vivo investigation of ASP1235 sensitivity. Their findings indicated that the THP-1 cell was a partially sensitive preclinical model to ASP1235. Next, the researchers evaluated the in vivo efficacy of ASP1235 in combination with venetoclax plus azacitidine using the THP-1 xenograft mouse model. The results showed that the combination therapy induced a significant reduction in tumor size compared to ASP1235 monotherapy and the other two drugs alone. This suggests that ASP1235 has an enhanced anti-tumor effect in combination with venetoclax and azacitidine.

“Consistent with in vitro observations in Figure 4, triple combination treatment with ASP1235, venetoclax and azacitidine induced tumor regression, and the anti-tumor effect of the triple combination was much stronger than that of ASP1235 single agent or venetoclax plus azacitidine without obvious body weight loss (Figure 5).”

Figure 5: ASP1235 showed enhanced anti-tumor effect in combination with venetoclax and azacitidine in THP-1 xenograft mouse model.

Conclusions

The findings of this study suggest that the combination therapy of ASP1235, venetoclax and azacitidine can be an effective treatment option for elderly patients or patients with chemotherapy R/R AML. This combination therapy induced a significant reduction in xenograft tumors in the THP-1 mouse model, suggesting that it may be a promising therapeutic approach for AML patients. Further clinical trials are needed to confirm these results.

“In conclusion, the triple combination treatment of ASP1235, venetoclax and azacitidine has the potential to benefit AML patients, and there is a possibility to expect the combination effect of ASP1235 and venetoclax regimen in FLT3 positive cancers beyond AML.”

Click here to read the full research paper published by Oncotarget.

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