Tagged: Trending With Impact

Oncotarget

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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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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Oncotarget

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.
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 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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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.”

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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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.
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 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.

For media inquiries, please contact media@impactjournals.com.

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.
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 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.

For media inquiries, please contact media@impactjournals.com.

Oncotarget

Plasma Growth Hormone in HCC: A Biomarker of Response to Atezo/Bev?

December 8, 2022

In a new study, researchers investigated the plasma growth hormone as a potential biomarker of response to atezolizumab and bevacizumab in advanced hepatocellular carcinoma patients.

Plasma Growth Hormone in HCC: A Biomarker of Response to Atezo/Bev?

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Hepatocellular carcinoma (HCC) is a highly aggressive cancer of the liver with a very poor prognosis; many patients pass away within a year of diagnosis. Currently, there is no effective screening method for HCC and thus, 80% of patients are diagnosed at advanced stages. This makes treatment difficult and often unsuccessful. As a result, new treatments for HCC are constantly being explored.

Atezolizumab and bevacizumab are two standard therapies used to treat unresectable, advanced HCC. However, researchers Yehia I. Mohamed, Dan G. Duda, Muhammad O. Awiwi, Sunyoung S. Lee, Lina Altameemi, Lianchun Xiao, Jeffrey S. Morris, Robert A. Wolff, Khaled M. Elsayes, Rikita I. Hatia, Aliya Qayyum, Shadi M. Chamseddine, Asif Rashid, James C. Yao, Armeen Mahvash, Manal M. Hassan, Hesham M. Amin, and Ahmed Omar Kaseb from MD Anderson Cancer Center, Massachusetts General Hospital, Harvard Medical School, Michigan State University, and University of Pennsylvania Perelman School of Medicine noticed a significant gap in research on biomarkers of response in advanced HCC patients treated with atezolizumab plus bevacizumab. The team conducted a new study aimed at beginning to close this gap. On December 6, 2022, their research paper was published in Oncotarget’s Volume 13, entitled, “Plasma growth hormone is a potential biomarker of response to atezolizumab and bevacizumab in advanced hepatocellular carcinoma patients.”

“This study investigated the biomarker value of plasma growth hormone (GH) level as a potential biomarker to predict outcome in unresectable HCC patients treated with current standard therapy, atezolizumab plus bevacizumab (Atezo/Bev).”

The Study

Plasma growth hormone (GH) is a potential biomarker that had not previously been evaluated in relation to this treatment regimen in HCC before. In this study, the researchers included 37 patients with advanced HCC. The patients received atezolizumab plus bevacizumab at the MD Anderson Cancer Center between June 2018 and November 2021. The median age of the patients was 67 years old, and the vast majority were male (83.8%). 

The team measured plasma GH levels, progression-free survival (PFS) and overall survival (OS). Plasma GH levels were measured by ELISA and used to stratify the HCC patients into GH-high and GH-low groups. The Kaplan-Meier method was used to calculate median OS and PFS. The Log-rank test was used to compare survival outcomes between GH-high and -low groups.

“To the best of our knowledge, this is the first study to assess clinical prognostic value of plasma GH level in patients who have received atezolizumab plus bevacizumab in clinical setting.”

The results of the study showed that plasma GH levels significantly correlated with OS. At the time of the analysis, the one-year survival rate was 70% among GH-low patients and 33% among GH-high patients. OS was significantly superior in GH-low compared to GH-high patients. PFS showed a non-significant trend in favor of GH-low patients compared to the GH-high group.

Conclusion

“Despite the small data size, plasma GH levels were strongly predictive of the disease outcome in patients treated with Atezo/Bev.”

The study concluded that plasma GH levels may be a promising biomarker for predicting response to atezolizumab plus bevacizumab in advanced HCC patients. Further, plasma GH levels may be used to stratify advanced HCC patients into high- and low-risk groups. The researchers recommend further research in larger scale and different populations to validate the findings and explore plasma GH levels as a potential biomarker of response to this treatment regimen in HCC.

“In conclusion, our study demonstrate[s] that plasma GH represents a candidate biomarker for predicting treatment outcomes in patients with advanced HCC treated with Atezo/Bev. Future studies in larger randomized clinical trial and with a more diverse ethnic, race, and gender background are warranted to further validate these findings.”

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

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Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

For media inquiries, please contact media@impactjournals.com.

Oncotarget

CRISPR Screens Identify Novel Targets for Personalized Cancer Therapy

October 7, 2022

In this trending new study, researchers used CRISPR-based genome-wide screens to identify genetic determinants of PARP10-mediated cellular survival.

CRISPR Screens Identify Novel Targets for Personalized Cancer Therapy
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Genetic interactions involved in the survival of cancer cells are potential therapeutic targets in personalized cancer therapy. “Synthetic lethal” is a type of genetic interaction where the knockout of one gene can cause cell death but only in the presence of another dependent gene. Cancer researchers view synthetic lethality screening as a powerful tool in precision medicine.

“Identifying genetic susceptibilities based on PARP10 expression levels is thus potentially relevant for finding new targets for precision oncology.”

Poly-ADP-ribose polymerase 10, or PARP10, is a nuclear protein that is overexpressed in multiple cancers. Genetic susceptibilities based on PARP10 expression levels in an individual may be potential targets for personalized cancer therapy. In a new study, researchers Jude B. Khatib, Emily M. Schleicher, Lindsey M. Jackson, Ashna Dhoonmoon, George-Lucian Moldovan, and Claudia M. Nicolae, from the Department of Biochemistry and Molecular Biology at Penn State College of Medicine, used CRISPR-based, genome-wide genetic screens to identify potential synthetic lethality interactions with PARP10-overexpressing and -knockout cancer cells. On September 28, 2022, their research paper was published in Oncotarget and entitled, “Complementary CRISPR genome-wide genetic screens in PARP10-knockout and overexpressing cells identify synthetic interactions for PARP10-mediated cellular survival.”

“Here, we employed complementary CRISPR loss-of-function genome-wide screening to identify genes required for proliferation of PARP10-overexpressing and PARP10-knockout cells.”

The Study

To identify potential synthetic lethal targets, the researchers conducted a CRISPR-based, genome-wide genetic screen of both PARP10-overexpressing and PARP10-knockout tumorigenic and non-tumorigenic breast cells. The screen looked for genes that were required for cell proliferation in the presence of PARP10 overexpression or PARP10 knockout.

“Here, we performed a series of CRISPR genome-wide loss-of-function screens in isogenic control and PARP10-overexpressing or PARP10-knockout cell lines, to identify genetic determinants of PARP10-mediated cellular survival.”

In the PARP10 overexpressing cells, the top results from their CRISPR screen were validated with biological pathway enrichment analyses, using both KEGG and Gene Ontology databases. A functional interaction between ATM and PARP10 expression was found. ATM promoted cell proliferation in PARP10-overexpressing cells.

In the genome-wide CRISPR knockout screens, genes required for the viability of PARP10-knockout cells were identified. In the PARP10 knockout cells, the top results from their CRISPR screen were validated with biological pathway enrichment analyses, using both KEGG and Gene Ontology databases. They identified the CDK2-Cyclin E1 complex as a genetic determinant for the proliferation of PARP10-knockout cells.

“Our work identifies a network of functionally relevant PARP10 synthetic interactions, and reveals a set of factors which can potentially be targeted in personalized cancer therapy.”

Conclusion

The researchers identified several genes that were differentially required for cell proliferation in the presence of PARP10 overexpression or knockout. Some of these genes have been previously implicated in cancer, while others were novel candidate cancer targets. The identification of these potential synthetic lethal interactions provides new insights into the role of PARP10 in cancer and may be useful for precision oncology. This study highlights the importance of using complementary CRISPR-based screens to identify potential cancer targets.

“We found that DNA repair factors, including ATM, a master regulator of the DNA damage checkpoint response, are specifically promoting the proliferation of PARP10-overexpressing cells. Moreover, we identified a role for PARP10 in regulating ATM recruitment to stressed replication forks. Finally, we found that the CDK2-cyclin E1 complex is specifically required for the proliferation of PARP10-deficient cells. Our work reveals novel PARP10 genetic interactions of functional relevance and identifies a set of factors which can potentially be targeted in personalized cancer therapy.”

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

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Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

For media inquiries, please contact media@impactjournals.com.

Oncotarget

Protein-Based Risk Model Predicts Esophageal Cancer Recurrence

September 23, 2022

Researchers developed a multi-protein expression-based risk model to predict recurrence-free survival for ESCC patients.

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Esophageal cancer is the sixth most common cause of death from cancer worldwide. The two main types of esophageal cancer are adenocarcinoma and esophageal squamous cell carcinoma (ESCC). ESCC arises from the cells lining the esophagus, and it is most common in areas of the world where tobacco use and alcohol consumption are high.

“Biomarkers to predict the risk of disease recurrence in Esophageal squamous cell carcinoma (ESCC) patients are urgently needed to improve treatment.”

Researchers Raghibul Hasan, Gunjan Srivastava, Akram Alyass, Rinu Sharma, Anoop Saraya, Tushar K. Chattopadhyay, Siddartha DattaGupta, Paul G. Walfish, Shyam S. Chauhan, and Ranju Ralhan from All India Institute of Medical Sciences, Mount Sinai Hospital Toronto, McMaster University, Guru Gobind Singh Indraprastha University, and the University of Toronto conducted a new study on the protein expression-based risk model they developed to predict recurrence-free survival for ESCC patients. On September 14, 2022, their research paper was published in Oncotarget’s Volume 13, and entitled, “Prediction of recurrence free survival for esophageal cancer patients using a protein signature based risk model.”

The Study

“Our study is important because: (i) it is based on changes in expression levels of the biomarker proteins in different subcellular compartments and is not limited to alterations in the overall protein expression levels; (ii) investigates the comprehensive clinical relevance of subcellular alterations in expression of multiple key components of Wnt pathway in the same ESCC patients’ cohort; (iii) correlates these findings with disease outcome and (iv) develops a Biomarker risk score for defining the risk of recurrence of ESCCs.”

Figure 1: Immunohistochemical analysis of Wnt protein in esophageal tissues.
Figure 1: Immunohistochemical analysis of Wnt protein in esophageal tissues.

The researchers aimed to develop and validate a panel of biomarkers with the potential to predict tumor recurrence in patients with ESCC, as well as to generate a risk model for clinical decision-making. This study enrolled 80 ESCC cases, 61 esophageal dysplastic tissues and 47 normal tissues. A multi-protein signature was generated from microarray data using the Cox proportional hazard model which was then internally validated on an independent set of samples by immunohistochemistry. The researchers demonstrated that a panel of four biomarkers (cytoplasmic β-catenin, nuclear c-Myc, nuclear DVL and membrane α-catenin) constituted the prognostic molecular signature for ESCC patients. They found that this protein signature could predict disease recurrence in patients with ESCC.

“Our panel of biomarkers predicted disease recurrence more effectively as compared to individual biomarkers analyzed in this study and demonstrated the strong predictive power of this panel of biomarkers for ESCC patients.”

Conclusion

The research team found that a panel of four biomarkers could predict disease recurrence in patients with ESCC. Furthermore, they showed that this protein signature could be used to stratify patients into high- and low-risk groups. This study provides valuable insights into the role of these proteins in the development and progression of esophageal cancer. The development of this risk model may help to tailor treatment and follow-up strategies for patients with ESCC.

“In conclusion, integrated analysis of expression of the panel of 4 proteins in ESCC patients has allowed us to validate the robustness of our biomarker panel in stratification of patients at high or low risk of disease recurrence. This risk classifier has the potential to identify the high risk patients for more rigorous personalized treatment and the low risk patients may be spared from the harmful side effects of toxic therapy as well reduce the burden on health care providers. The findings of our study set the foundations for external validation of the prognostic signature as a step forward in translation of this panel of protein markers for ESCC patients and establish their clinical relevance for larger worldwide application in future studies.”

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

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Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

For media inquiries, please contact media@impactjournals.com.

Oncotarget

Does a Mechanism Linking Cellular Aging to Cellular Quiescence Exist?

August 5, 2022

Researchers found that diverse geroprotectors differently affect a mechanism linking cellular aging to cellular quiescence in budding yeast.

Saccharomyces cerevisiae
Saccharomyces cerevisiae yeast budding cell under the microscope.

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The mechanisms of cellular aging and cellular quiescence have been preserved throughout evolution. Cellular quiescence is a temporary state of cell cycle arrest and low metabolic activity. Importantly, quiescent (Q) cells maintain the ability to quickly activate and re-enter the cell cycle (in response to the appropriate stimuli). Recent research has shown that cellular quiescence may play a role in cellular aging. 

In a 2020 study, research findings indicated that the rate at which yeast cells age is determined by a complicated program that affects 1) when a state of quiescence is entered, 2) how long quiescence is maintained and 3) when the cell exits quiescence. Researchers found that caloric restriction (CR) (a geroprotective intervention) appears to remodel this program, and this remodeling could be responsible for the CR-dependent delay of yeast chronological aging. Thus, the researchers considered the question: Does a single mechanism exist which links cellular aging to cellular quiescence? 

“We have introduced a new yeast model for studying mechanisms linking cellular aging to cellular quiescence [109, 110].”

In a new study, researchers (Anna Leonov, Rachel Feldman, Amanda Piano, Anthony Arlia-Ciommo, Jennifer Anne Baratang Junio, Emmanuel Orfanos, Tala Tafakori, Vicky Lutchman, Karamat Mohammad, Sarah Elsaser, Sandra Orfali, Harshvardhan Rajen, and Vladimir I. Titorenko) from Concordia University, Montreal, used a new yeast model to test their hypothesis that a mechanism exists linking cellular aging to cellular quiescence. On July 28, 2022, their research paper was published in Oncotarget and entitled, “Diverse geroprotectors differently affect a mechanism linking cellular aging to cellular quiescence in budding yeast.”

Caloric Restriction Delays Cellular Aging by Quiescence Program Changes

“Our hypothesis posits that this mechanism integrates four different processes, all of which are initiated after yeast cells cultured in a medium initially containing glucose consume it.”

In a 2017 study, researchers cultured yeast in a medium initially containing 0.2% glucose (CR). After consuming the glucose, the cells began to differentiate into quiescent and non-quiescent cell populations. Quiescent cells that developed in these cultures had different buoyant densities and could be separated into high- and low-density sub-populations. 

CR delayed yeast chronological aging by causing specific changes in four processes of a cellular quiescence program. Process one consists of a cell-cycle arrest and leads to the formation of high-density Q cells. Process two is the conversion of high-density Q cells into low-density Q cells. Processes three and four are the fast or slow decline of quiescence in low- or high-density Q cells, respectively. The researchers believe that these processes could converge into a mechanism that links cellular aging to cellular quiescence in chronologically aging budding yeast.

Figure 1: A hypothetical model for the four processes linking cellular aging to cellular quiescence. 
Figure 1: A hypothetical model for the four processes linking cellular aging to cellular quiescence. 

How do Other Geroprotectors Change the Quiescence Program?

“Here, we tested our hypothesis by assessing how four different geroprotectors influence the four processes that could link cellular aging to cellular quiescence.”

In the current study, the team’s first objective was to compare the effects of four different geroprotectors on the four quiescence processes. CR, lithocholic acid (LCA) and the single-gene deletion mutations tor1Δ and ras2Δ all delay chronological aging and extend the longevity of S. cerevisiae. Geroprotectors other than CR were examined in each of the four processes. They found that these geroprotectors differently affected processes one and two and decelerated processes three and four. Two ways of slowing down yeast chronological aging were determined by testing the four geroprotectors. One way was specific to CR and the ras2Δ mutation, and the other way was characteristic for LCA and the tor1Δ mutation.

“We selected CR and LCA to investigate the two ways different geroprotectors postpone yeast chronological aging by differently targeting the mechanism potentially linking cellular aging to cellular quiescence.”

They hypothesized that the abilities of CR and LCA to regulate the four processes of a cellular quiescence program are the same used to slow yeast chronological aging. Their next objective was to test the hypothesis that specific metabolic Q cell traits can contribute to the different effects of CR and LCA on processes one and two and their similar effects on processes three and four. Two CR-specific changes in metabolic traits of Q cells were assessed: increased intracellular concentrations of glycogen and trehalose within Q cells. 

“Therefore, we assessed the contributions of the increased intracellular concentrations of glycogen and trehalose within Q cells to the CR- and LCA-driven changes in cellular quiescence and to the CR- and LCA-promoted slowdowns of yeast chronological aging.”

Cellular Aging Delayed in Two Different Ways

In summary, study results showed that both ​​CR and the ras2Δ mutation stimulated the development of high-density Q cells (process 1) and decelerated yeast chronological aging by arresting the cell cycle in early G1, whereas LCA and the tor1Δ mutation did so by arresting the cell cycle in late G1. Both ​​CR and the ras2Δ mutation promoted an age-related conversion of high-density Q cells into low-density Q cells (process 2), whereas LCA and the tor1Δ mutation postponed this conversion. All four geroprotective interventions delayed a fast aging-associated deterioration in the quiescence of low-density Q cells (process 3) and postponed a slow aging-associated decline in the quiescence of high-density Q cells (process 4).

It is possible that the different ways these geroprotectors regulate the first two processes do not contribute to the aging-delaying capabilities of these geroprotectors. However, the researchers in this study believe there are two different ways of employing geroprotector-dependent changes in the first two processes that decelerate yeast chronological aging. They also found that a rise in trehalose within quiescent yeast contributes to chronological aging and quiescence maintenance.

“The second line of evidence for the existence of a mechanism linking cellular aging to cellular quiescence comes from our observation that an increase in intracellular trehalose within Q cells is an essential contributor to both chronological aging and quiescence maintenance in S. cerevisiae.”

Figure 6: A model for the two different ways of delaying yeast chronological aging by geroprotectors that differently affect the mechanism potentially linking cellular aging to cellular quiescence.
Figure 6: A model for the two different ways of delaying yeast chronological aging by geroprotectors that differently affect the mechanism potentially linking cellular aging to cellular quiescence.

Conclusion

“This study and our previously published data [109] provide conclusive evidence for the existence of a mechanism that links cellular aging to cellular quiescence in chronologically aging S. cerevisiae. The mechanism integrates processes 1, 2, 3 and 4 discussed above in the text and schematically depicted in Figures 1 and 6.”

Collectively, these data provide conclusive evidence for a mechanistic link between cellular aging and cellular quiescence. In the future, the researchers aim to better understand how to target the cellular quiescence program in order to delay cell aging and the onset of aging-related diseases.

“In conclusion, because the mechanisms of cellular aging and cellular quiescence are evolutionarily conserved [1, 3, 62, 66], this study makes an important next step toward the understanding of how the knowledge-based targeting of cellular quiescence can be used for slowing down cellular and organismal aging and for delaying the onset of aging-associated diseases.”

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

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Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

For media inquiries, please contact media@impactjournals.com.

Oncotarget

How Heartburn Can Turn Into Esophageal Cancer, and a Possible Biomarker

July 15, 2022

In a recent Oncotarget paper, researchers investigated telomere shortening in patients with Barrett’s esophagus as a potential biomarker of high risk for esophageal cancer.

Acid reflux / heartburn

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Smokers are significantly more likely than nonsmokers to have acid reflux. In many Western countries, a popular diet—known for its convenience, availability and, frankly, its lack of nutritional value—is also known to cause acid reflux. Some of the affordable foods and beverages easily accessible to Western consumers include fried food, fast foods, pizza, potato chips (and other processed snacks), high-fat meats (bacon, sausage), cheese, alcohol, soda, energy drinks, and etcetera. Unfortunately, this indulgent type of diet is accompanied by consequences beyond oily skin and an expanding waistband.

Barrett’s Esophagus

Chronic acid reflux can lead to gastroesophageal reflux disease. Gastroesophageal reflux disease can lead to Barrett’s esophagus (BE). BE is a premalignant condition in which the lining of the esophagus becomes damaged by acid reflux. BE can lead to the onset of a type of cancer called esophageal adenocarcinoma (EAC). Over the past few decades, statistics have reported that the incidence of EAC in Western populations is increasing.

“Esophageal adenocarcinoma (EAC) is on the rise in western countries with increased incidence and high mortality [1, 2].”

Since the popularity of smoking and a heartburn-inducing diet is likely to continue in the West, the early detection of EAC is critical for improving patient outcomes. If a biomarker could indicate a BE patient’s present risk of EAC, early EAC treatment could curb incidence and mortality rates. However, such a biomarker has yet to be confirmed. On February 14, 2022, researchers from Technische Universität München, Columbia University Irving Medical Center and Universitätsklinikum Freiburg published the research paper, “Telomere shortening accelerates tumor initiation in the L2-IL1B mouse model of Barrett esophagus and emerges as a possible biomarker,” in Oncotarget.

“Here we aimed to provide functional evidence for the hypothesis that telomere shortening can directly contribute to tumor initiation, and thus serve as a potential biomarker for BE cancer risk stratification [22, 24].”

Telomere Shortening and Tumor Initiation

“Shortened telomeres is a common sight in epithelial cancers and has also been described in EAC and its precancerous lesions.”

In this study, researchers investigated the impact of shortened telomeres in a mouse model for Barrett’s esophagus (L2-IL1B). The L2-IL1B mouse model is characterized by inflammation that leads to a Barrett-like metaplasia. The team knocked out the mTERC gene (mTERC−/−), which is the catalytic subunit of telomerase in the L2-IL1B mice. 

After mTERC knockout, the researchers found that the telomeres shortened and the mice displayed signs of DNA damage. The tumor area along the squamocolumnar junction (SCJ) was increased in the second generation of these mice, and histopathological dysplasia (abnormal changes) was also increased. In vitro studies indicated that organoid formation capacity increased in BE tissue from the L2-IL1B mTERC−/− G2 mice.

“In summary, we here demonstrated a functional role of telomere shortening, a well observed property of BE, in promoting early onset esophageal tumor initiation in the L2-IL1B mouse model.”

Additional results of the study found that the telomeres in human BE epithelial cells lining the stomach with or without dysplasia were shorter than in gastric cardia tissue (the junction between the lower esophagus and the stomach). The study also found that differentiated cells that make mucus (goblet cells, which help protect the stomach lining) had longer telomeres than cells actively dividing (and more likely to become cancerous) in the columnar lined BE epithelium. 

“Moreover, besides the importance during early carcinogenesis in the mouse model, shortening of telomeres was specifically decreased in dysplastic columnar-type tissue rather than in differentiated goblet cells in human BE- and LGD tissue samples.”

Conclusion

“Here, we demonstrate that telomere dysfunction aggravates the histological phenotype, extends the tumor area in the inflammation-based L2-IL1B mouse model for BE and acts as a driver for early dysplasia development.”

In summary, these findings suggest that shortened telomeres may play a role in tumor development in a mouse model of BE and are associated with proliferating columnar epithelium in human BE. The study suggests that shortened telomeres should be evaluated further as a possible biomarker for predicting EAC cancer risk in people with BE.

“It is plausible that with our measurements we could emulate this with shortened telomeres being at higher risk of genome instability and lowered cell-to-cell variability marking clonal expansion. However, larger studies are needed to test these hypotheses.”

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

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Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

For media inquiries, please contact media@impactjournals.com.