Author: The Wistar Institute

The Wistar Institute Appoints Italo Tempera, Ph.D., as Associate Director for Cancer Research Career Enhancement of Its Cancer Center

Written by The Wistar Institute on August 31, 2021. Posted in Press Releases.

PHILADELPHIA — (Aug. 31, 2021) — The Wistar Institute announces the appointment of Italo Tempera, Ph.D., as Associate Director for Cancer Research Career Enhancement at the Institute’s Cancer Center. In this role, Tempera, who is also an associate professor in the Gene Expression & Regulation Program, will lead the educational mission of the Institute and its Cancer Center to train scientists and create workforce development programs in the life sciences.

Tempera will be working closely with Cancer Center faculty and the Dean of Biomedical Studies to coordinate the diverse Cancer Center educational initiatives, expanding and strengthening partnerships for high-school, undergraduate, graduate and postdoctoral training programs in cancer biology.

Graduate and postdoctoral training programs leverage Wistar’s close collaborations with neighboring and international world-renowned academic institutions, including the University of Pennsylvania, Drexel University, University of the Sciences, University of Bologna, Italy, and Leiden University, Netherlands, for experiential training in Wistar laboratories.

Wistar’s Biomedical Technician Training (BTT) Program and Biomedical Research Technician (BRT) Apprenticeship, built on meaningful collaborations with the Community College of Philadelphia, Cheyney University and a growing list of partnering educational institutions and biotechnology companies, are uniquely tailored to support talent development, customized skills and workforce training to best prepare students for job opportunities in the life sciences ecosystem.

“We are grateful to Italo for taking on this role that comes with important responsibilities for the cultivation of scientific talent and the training of future generations of cancer researchers,” said Dario Altieri, M.D., president and CEO of The Wistar Institute, director of the Cancer Center and the Robert & Penny Fox Distinguished Professor.

Tempera’s research is focused on the Epstein Barr virus (EBV) and how it regulates expression of its genes in the host cell during infection. Since EBV infection has a causative role in the development of some types of cancer in people with a compromised immune system, the Tempera lab aims at disrupting the natural capacity of EBV to modulate gene expression as a new approach for treating EBV-associated cancers.

“This is a time of substantial growth across Wistar’s education programs and I am thrilled by the opportunity to play a part in this process,” said Tempera. “Looking back to my own early career steps, education and training are probably the most exciting periods for a scientist, because they come with the realization of the vast potential for their career growth and for their ability to make impactful discoveries.”

Tempera graduated with a B.Sc. in molecular biology and a Ph.D. in biochemistry from the Sapienza University of Rome, Italy. Before joining Wistar in 2020, he was an associate professor at the Lewis Katz School of Medicine of Temple University.

###

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Wistar Welcomes Assistant Professors Amelia Escolano, Ph.D., and Nan Zhang, Ph.D.

Written by The Wistar Institute on August 31, 2021. Posted in Featured News.

Wistar is pleased to welcome two new assistant professors starting September 1.

Dr. Amelia Escolano researches new vaccine approaches against highly mutating viruses. She will join the Vaccine & Immunotherapy Center.

“I am thrilled to have the opportunity to develop my own scientific ideas and create a community of researchers around them,” said Dr. Escolano. “I look forward to establishing new collaborations and exploring new branches of my research at Wistar, and am excited to have a platform from which I will be able to support women in science.”

Dr. Nan Zhang studies the role of immune cells called macrophages in ovarian cancer metastasis to find new therapies for this disease. He will join the Immunology, Microenvironment and Metastasis Program of the Cancer Center.

“Learning how to be proficient at securing funding for my lab, hiring and managing staff are big responsibilities,” Dr. Zhang said. “But these challenges bring some of the most thrilling adventures one could ever have — making new discoveries that can potentially save people’s lives and mentoring next-generation scientists.”

The Institute’s faculty continues to expand to include new relevant expertise and strengthen our scientific efforts on the forefront of cancer, immunology and infectious disease research.

Wistar Scientists Unveil Mechanism That Stops Cancer Progression by Interfering With Cancer Cell Metabolism

Written by The Wistar Institute on August 25, 2021. Posted in Featured News.

During progression from a precancerous lesion to an aggressive tumor and then metastasis, cancer cells rewire their metabolism to support increased energy demands due to continuous growth and adapt to unfavorable conditions in the surrounding environment.

In a study published in the journal Science Advances, Dr. Altieri and colleagues discovered a new mechanism that suppresses tumor development by interfering with metabolism and with the function of mitochondria, the cell’s powerhouse.

Understanding Parkin

The team studied a gene called Parkin that is known for its protective function in brain cells and is altered in Parkinson’s disease. Previous evidence indicated that Parkin might have a role in regulating cancer cell metabolism and suppressing tumor growth, but the mechanism remained elusive.

The team found that Parkin expression was low or undetectable in tumors compared with their respective normal counterpart.

When they re-introduced Parkin in prostate cancer cells and other cancer cell types that did not express the protein, they observed reduced cell movement and a blocking of invasion, while deletion of Parkin in normal cells increased cell motility.

In vivo, Parkin-expressing prostate cancer cells formed smaller tumors and had lower metastatic potential.

Role of Parkin and Mitochondria

The Altieri lab has contributed important knowledge in the role mitochondria play in cancer, showing that changes in their size, shape and distribution within cells increase their ability to move and invade other tissues and acquire other aggressive traits.

In the new study, they discovered that Parkin interferes with the function of mitochondria in cancer cells, and, as a consequence, blocks tumor cell motility, which is critical for their ability to disseminate and invade other tissues during metastasis.

Forced Parkin expression in cancer cells also resulted in reduced energy production.

In addition, researchers found that exposing Parkin-expressing cancer cells to stress conditions such as nutrient deprivation and DNA-damaging agents resulted in a strong increase in Parkin levels.

From this study, Parkin emerges as a critical, stress-activated effector of a tumor suppression pathway that stops cancer progression and metastasis by interfering with the ability of cancer cells to reprogram their metabolism.

Wistar Scientists Unveil Widespread Tumor Suppression Mechanism That Stops Cancer Progression by Interfering With Cancer Cell Metabolism

Written by The Wistar Institute on August 25, 2021. Posted in Press Releases.

PHILADELPHIA — (Aug. 25, 2021) — According to a study by The Wistar Institute, the tumor suppressor Parkin, whose levels are reduced in different cancer types, causes acute metabolic and oxidative stress, suppresses mitochondrial trafficking, and blocks tumor cell movement, reducing primary and metastatic tumor growth. These findings, published today in Science Advances, demonstrate that metabolic and mitochondrial reprogramming, which are well-established hallmarks of tumor progression, act as potent drivers of disease.

“We’ve known for a century that progression from a small, premalignant lesion to an aggressive tumor and then metastasis is accompanied by changes in metabolism that allow cancer cells to support increased energy demands due to continuous growth and adapt to unfavorable microenvironment conditions,” said study lead author Dario C. Altieri, M.D., Wistar president and CEO, director of the Institute’s Cancer Center and the Robert & Penny Fox Distinguished Professor. “Our study provides evidence that reprogramming the metabolic and mitochondrial function is a cancer-promoting factor opposed by tumor suppression mechanisms, and we identified one that is relevant to halting several different types of cancer.”

Altieri and colleagues studied a gene called Parkin that is altered in Parkinson’s disease. Through a degradation mechanism called mitophagy, Parkin was known to protect brain cells by facilitating selective removal of damaged mitochondria, the organelles that produce energy. Previous evidence indicated that Parkin might have a role in regulating cancer cell metabolism and suppressing tumor growth, but the mechanisms remained elusive.

Researchers re-introduced Parkin in prostate cancer cells and other cancer cell types that did not express the protein and observed reduced cell movement and a blocking of invasion. Concordantly, deletion of Parkin in normal cells increased cell motility.

In vivo, Parkin-expressing prostate cancer cells formed smaller tumors and had lower metastatic potential.
The team found that Parkin expression was low or undetectable in patient-derived tissue samples and cancer cell lines and decreased in all the tumor types contained in The Cancer Genome Atlas database compared with their respective normal counterpart.

A global proteomic study of cancer cells modified to express Parkin revealed alterations in the protein networks that control cell movement and metastasis and decreased oncogenic signaling.

Importantly, these effects were independent of Parkin’s role in mitophagy in response to mitochondrial damage. Researchers then asked whether other pathological conditions could activate Parkin. They found that exposing Parkin-expressing cancer cells to stress conditions such as nutrient deprivation and DNA-damaging agents resulted in a strong increase in Parkin levels.

Parkin functions as an enzyme that promotes ubiquitination, a process that modifies proteins to flag them for degradation. Researchers observed that this function is required for Parkin’s tumor suppressive activity.

Forced Parkin expression in cancer cells alters ubiquitination in protein networks that control cell death, mitochondrial function and glucose metabolism. As a consequence, Parkin interferes with movement of mitochondria within the cells, which affects their function in tumor progression.

“Our lab has described the role these organelles play in cancer, showing that changes in mitochondrial size, shape and distribution within the cells allow for increased cell motility, metastatic dissemination and other aggressive disease traits,” said Ekta Agarwal, Ph.D., first author of the study and a postdoctoral fellow in the Altieri lab. “This new study shows how a tumor suppressor pathway opposes mitochondrial dynamics to counteract cancer progression.”

Researchers further dissected the mechanism of Parkin tumor suppression and its role in controlling metabolism, and demonstrated that Parkin expression blocks an enzyme called transketolase (TKT) that is involved in glycolysis, a metabolic pathway specifically used by cancer cells to generate energy. This block results in reduced energy production.

TKT also plays a key role in counteracting oxidative stress in the cell. Therefore, another consequence of its inhibition is buildup of reactive oxygen species and oxidative stress in the mitochondria, which inhibit mitochondrial function and, in turn, tumor cell motility.

From this study, Parkin emerges as a critical, stress-activated effector of a tumor suppression pathway that antagonizes malignant cell proliferation and metastatic competence by interfering with the ability of cancer cells to reprogram their metabolism.

Co-authors: Aaron R. Goldman, Hsin-Yao Tang, Andrew V. Kossenkov, Jagadish C. Ghosh, and David W. Speicher from Wistar; Lucia R. Languino from Thomas Jefferson University; and Valentina Vaira from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy and University of Milan, Italy.

Work supported by: National Institutes of Health (NIH) grants P01 CA140043, R35 CA220446, R50 CA221838, R50 CA211199 and S10 OD023586. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.

Publication information: A Cancer Ubiquitome Landscape Identifies Metabolic Reprogramming as Target of Parkin Tumor Suppression, Science Advances (2021). Online publication.

###

The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. Wistar’s Business Development team is dedicated to accelerating the translation of Wistar discoveries into innovative medicines and healthcare solutions through licensing, start-ups and creative collaborations. wistar.org.

Scientist Luis Montaner smiles in a Wistar lab

The BEAT-HIV Collaboratory Receives More Than $29 Million in NIH Funding for HIV Cure Research

Written by The Wistar Institute on August 17, 2021. Posted in Press Releases.

PHILADELPHIA — (Aug. 17, 2021) — The Wistar Institute announces that the National Institutes of Health (NIH) granted a five-year, $29.15 million Martin Delaney Collaboratories for HIV Cure Research award to the BEAT-HIV Martin Delaney Collaboratory to advance research towards a cure for HIV-1 Infection by Combination Immunotherapy. This funding extends a grant originally awarded in 2016 based on research progress to date.

Philadelphia-based BEAT-HIV Martin Delaney Collaboratory is a consortium of more than 70 top HIV researchers spearheaded by principal investigator Luis J. Montaner, D.V.M., D.Phil., Herbert Kean, M.D., Family Professor and chair of the HIV Research Program at The Wistar Institute Vaccine & Immunotherapy Center, and co-led with James L. Riley, Ph.D., a professor of Microbiology at the Perelman School of Medicine at the University of Pennsylvania, and Robert Siliciano, M.D., Ph.D., professor at the Johns Hopkins University School of Medicine. They are working to identify the most effective way to combine different immunotherapy regimens to cure HIV. BEAT-HIV consists of a large international group of investigators from academic, community-based organizations, and industry, and includes research teams from The Wistar Institute, the University of Pennsylvania, Philadelphia FIGHT, and others.

“In the five years since its establishment, the BEAT-HIV Delaney team has made significant advances to better understand the mechanisms of HIV latency and test combinations of immunotherapy approaches to get us closer to a cure for HIV,” said Montaner. “In spite of the COVID-19 pandemic, we advanced HIV cure-directed research and successfully launched clinical trials with persons living with HIV in Philadelphia to test novel strategies to achieve an HIV cure. The new grant will make it possible to test added clinical strategies and expand our ongoing studies based on what we have learned.”

The new funding will support research articulated in three main aims: understanding the basic mechanisms underlying persistence of the viral reservoir; achieving durable suppression of HIV replication in the absence of ART; and developing new approaches to eradicate the HIV reservoir.

“Importantly, the new award will include an academic, community and industry coalition to advance HIV cure-directed research using cell therapy as the only reported strategy resulting in an HIV cure,” said Riley.

Through long-term partnerships with community groups like Philadelphia FIGHT, a comprehensive AIDS care and service organization, and with the BEAT-HIV Community Advisory Board, the Collaboratory will continue to raise awareness of HIV cure efforts in Philadelphia and nationally through outreach efforts.

“The new award is a continuation of an alliance and represents strong community ties that support these researchers,” said Jane Shull, executive director at Philadelphia FIGHT. “Active research participation by persons living with HIV is required for scientific advances and community voices help shape the science being done. The BEAT-HIV team includes this local, active and committed community working in partnership with the research team, which is central to its success.”

First goal of the grant is to understand the basic mechanisms underlying persistence of the viral reservoir during ART, what cell populations contribute to rebound after treatment interruption, and the role played by host-related factors.

The insight gained from this research will be key for the second goal of developing strategies to achieve durable suppression of HIV replication in the absence of ART. This effort will also build upon the advances in clinical research on broadly neutralizing antibodies (bNAb) to neutralize multiple HIV strains and target conserved regions of the virus to help the immune system control viral production and remove infected cells. BEAT-HIV researchers will capitalize on advances in this area by testing synthetic DNA technology to better deliver the genetic blueprint for the body to make different specific bNAbs simultaneously. When used as combination antibody immunotherapy, bNAbs are known to be effective in controlling HIV. An additional approach to be tested will be to boost natural killer and T cell responses to achieve long-term viral suppression. Eventually, the two strategies will be combined to maximize long-term control potential.

The third goal of the BEAT-HIV Martin Delaney Collaboratory will be to develop new approaches to eradicate the HIV reservoir. Strategies to be tested will include novel drugs able to reactivate latent HIV hiding in the immune cells, combined with gene therapy designed to change a person’s killer T cells to make them able to find infected cells more efficiently via a chimeric antigen receptor (CAR). In addition, researchers will apply the mRNA-LNP technology used to create COVID-19 mRNA vaccines as a strategy to directly make cells resistant to HIV. The ultimate goal is to identify which approaches have the best potential and test them in combination to achieve complete HIV eradication.
The Collaboratory also includes researchers from University of California, San Diego; Harvard Medical School; The Rockefeller University; Rush University; University of North Carolina at Chapel Hill; Duke University; Fred Hutchinson; NIH; Merck & Co.; Accelevir Diagnostics, LLC; University of Washington; and Instituto Nacional de Enfermedades Respiratorias (INER), Mexico.

In 2020, more than 37 million people were living with HIV and 27.5 million were receiving antiretroviral therapy (ART) worldwide. The Martin Delaney Collaboratories for HIV Cure Research program was established in 2011 by the NIH to accelerate the pace of HIV cure research.

Thanks to the advances in ART treatments, people with HIV can live long and healthy lives, but their bodies can’t eliminate the virus, which remains silent in some immune cells and rebounds from this hidden reservoir if medication is stopped.

Click here to view the full NIAID release.

Congratulations BTT Program and BRT Apprenticeship Graduates!

Written by The Wistar Institute on August 16, 2021. Posted in Featured News.

On August 12, Wistar hosted a ceremony for the Biomedical Technician Training (BTT) Program graduates of 2020 and 2021 and the Biomedical Research Technician (BRT) Apprenticeship graduates of 2021.

Dr. Dario Altieri, Wistar president and CEO, welcomed students and attendees.

“Having an opportunity to share our passion for science with students and trainees from the Community College is always a privilege and an honor,” Dr. Altieri said. “We hope the tools and knowledge you’ve been exposed to are going to stay with you for a long time and will work as a key to unlock a career in the life sciences.”

Dr. Bill Wunner, director of Academic Affairs, Outreach Education and Technology Training, founded the BTT Program at Wistar.

“I have had a long establishment with this training opportunity and value it tremendously from the point of view of seeing people become successful,” he said.

He addressed the trainees and urged them to think about their plans for the future: What success looks like to them, what they want to be, and what knowledge and tools they need to get there.

“To turn your aspirations into reality, you need a team of trusted advisors — be sure that one of those mentors is going to be your champion in your next steps,” he said. “And chase the goal of continuously learning.”

Dr. Kristy Shuda McGuire introduced three graduates, one from each class, who gave inspiring speeches about their experience in the Programs, their aspirations after graduating and the opportunities that opened up for them through this training experience.

She explained how the class of 2021 was supposed to start the BTT Program in May of 2020, when the pandemic hit. Wistar felt strongly about keeping that promise and made sure the trainees finished the Program by August 2021. This prompted development of an accelerated version of the BTT Program, which included updated curriculum and two internships, one in an academic lab and one in an industry lab.

“We are delighted that 100 percent of these 12 students are either continuing their education or taking laboratory positions or both.”

Keynote speaker Calvin R. Snowden, Jr., managing partner at CBS BioPharma, took the audience through his career journey in the life sciences to highlight the importance of taking advantage of new opportunities and all chances to advance one’s education and never being afraid to ask questions.

“When you enter a new work environment, tell yourself that you belong and deserve to be there, because you have the skills and ability,” said Snowden. “Don’t let anyone take that away from you, and you will be successful.”

He also remarked on the power of mentorship and let the graduates know that he, and everyone at Wistar and the collaborating institutions that host BTT and BRT interns, are there for them throughout their future careers.

Click here to watch the event recording and listen to the full speeches.

Completion Ceremony of the Biomedical Technician Training Program and the Biomedical Research Technician Apprenticeship: Class of 2020 and 2021

This event was held in hybrid form and all in-person participants provided proof of vaccination, completed a temperature check, and were socially distant during the event.

The Wistar Institute Recruits Daniel Claiborne, Ph.D., as Caspar Wistar Fellow

Written by The Wistar Institute on July 30, 2021. Posted in Press Releases.

PHILADELPHIA — (July 30, 2021) — The Wistar Institute, an international biomedical research leader in cancer, immunology and infectious diseases, announces the appointment of Daniel Claiborne, Ph.D., as Caspar Wistar Fellow in the Vaccine & Immunotherapy Center (VIC).

Claiborne studies the complex interplay between virus and host in HIV infection, with focus on developing optimized chimeric antigen receptor (CAR) T cell therapy for a functional HIV cure using innovative model systems.

“The Wistar VIC has a long-standing commitment to finding a cure for HIV by exploring the potential of the human immune system in fighting the disease,” said Dario Altieri, M.D., Wistar president and CEO, director of The Wistar Institute Cancer Center and the Robert and Penny Fox Distinguished Professor. “Dan will integrate his CAR T cell expertise into our HIV research program and further his innovative approach as a tool to detect and target the hidden virus reservoirs, with the goal of achieving a functional cure.”

CAR T cells represent a powerful immunotherapy approach for blood cancer, based on engineering a patient’s own T cells to recognize and eliminate malignant cells. This strategy is also being applied to target HIV-infected cells and several anti-HIV CAR T cells have been successfully tested in preclinical models.

Natural mechanisms built to prevent autoimmunity dampen the T cell response in the presence of prolonged antigen exposure, for example in cancer and chronic viral infections. This drawn out state leads to T cell exhaustion. Claiborne’s research aims at gaining a deeper understanding of these mechanisms that may hinder the success of T cell immunotherapies, which is critical to developing next-generation CAR T cell therapies for the treatment of HIV as well as cancer.

“I am beyond thrilled by the opportunity to launch my research career at a place like Wistar that is home to one of the most productive HIV research programs in the nation and traditionally has a strong focus on immunology,” said Claiborne. “With its advanced technological capabilities and collaborative approach to science, I think this is the ideal setting for me to develop my research.”

Claiborne’s recruitment was made possible through the Caspar Wistar Fellows Program that supports outstanding junior scientists in the early stages of their career as independent investigators.

“We are very excited to welcome Dan Claiborne to our faculty and grateful to Doug Briggs and his wife Peggy for making it possible,” added Altieri. “We look forward to Dan’s success and achievements as he reaches his full scientific potential.”

Claiborne earned his B.S. in biochemistry from Florida State University and a Ph.D. in immunology and molecular pathogenesis from Emory University. Before joining Wistar, he was a postdoctoral researcher at the Ragon Institute of MGH, MIT and Harvard.

###

Wistar Scientists Described Fundamental Gene Expression Mechanism With Implications in Immunity and Cancer

Written by The Wistar Institute on July 23, 2021. Posted in Featured News.

In a recent Cell Reports paper, Dr. Bin Tian and team revealed a mechanism that has far-reaching implications in development and diseases, including immunity and cancers.

The lab studies RNA biology to understand just how gene expression is regulated at the RNA level.

The genetic code of DNA to RNA and proteins is fine-tuned at different stages. Most control mechanisms take place after RNA is made.

Tian and colleagues focus on a mechanism called alternative polyadenylation (APA) that modifies the tail end of RNA sequences to generate multiple messenger RNAs from the same gene, which scientists call isoforms. This dramatically increases the complexity of our genome, so that fewer genes are needed to encode all the proteins a cell needs.

Though this mechanism affects more than half of human genes, its significance was poorly understood.

However, the lab uncovered the role APA plays in facilitating protein production in certain sites within the cell where those proteins are most needed.

“When mRNAs leave the nucleus and move to the cytoplasm, they need to be properly directed to reach the appropriate site of protein translation,” said Dr. Tian. “The cytoplasm is a huge space for an RNA molecule: For comparison, imagine entering a baseball stadium and needing directions to reach your seat.”

Researchers discovered that APA directs certain messenger RNAs to the endoplasmic reticulum (ER), a network of tubes that build, package and transport proteins. They also found that specific sequences and structures within the messenger RNAs determine their potential to undergo APA and ultimately associate with the ER.

These mRNAs tend to encode for signaling proteins, which help cells communicate with each other by sending, receiving, and processing signals in response to changes in the environment.

Dr. Tian and his team hypothesize that association with the ER anchors certain mRNA isoforms in specific cellular locations where important signaling events happen, making the whole process more efficient.

“According to our model, the ER would serve as a scaffold to keep proteins ‘on hand’ where they are most needed,” said Tian. “This would provide a platform for signaling events to happen effectively at the right place in the cell.”

This study has far-reaching implications in development and disease, including immunity and cancer. The Tian lab is exploring approaches to regulate APA as a new therapeutic modality.

To learn more about the study, read our press release.

Wistar Scientists Discovered Fundamental and Widespread Gene Expression Control Mechanism that Potentially Creates Proteins at Distinct Locations in the Cell, with Implications in Immunity and Cancers

Written by The Wistar Institute on July 20, 2021. Posted in Press Releases.

PHILADELPHIA — (July 20, 2021) — Alternative polyadenylation (APA) is an RNA processing mechanism that regulates gene expression by generating different ends on RNA transcripts of the same gene. Though it affects more than half of human genes, the significance of APA was poorly understood. Now a new study by The Wistar Institute describes an important function of APA in allowing certain mRNAs to reach specific sites of protein synthesis and reveals that length, sequence and structural properties can determine the destination (and fate) of mRNAs within the cell. These findings, published online in the journal Cell Reports, shed light on the consequences of APA that may represent a paradigm shift in the mRNA metabolism field.

The laboratory of Bin Tian, Ph.D., professor and co-leader of the Gene Expression & Regulation Program at The Wistar Institute Cancer Center and senior author on the study, was among the first to discover the widespread occurence of APA using genomic and bioinformatic approaches.

Following gene transcription, messenger RNAs are chemically modified to become mature RNA molecules that can leave the nucleus and perform their functions. One of these modifications is polyadenylation, which prevents RNA degradation and favors its translation into protein.

Through APA, a gene can be polyadenylated at multiple sites, resulting in mRNAs with different coding sequences and/or regulatory regions (3’untranslated regions or 3’UTRs), called isoforms. Transcripts encoding the same protein can have different fates in the cell because of distinct 3’UTRs, which harbor regulatory elements for mRNA metabolism. This dramatically increases the complexity of our genome, so that fewer genes are needed to encode all the proteins a cell needs.

Tian and colleagues employed functional genomics methods to analyze the distribution of the APA isoforms in mouse cells. Bioinformatic analysis and machine learning approaches revealed that APA, via modulation of mRNA 3’UTRs, impacts the connection between mRNAs and the endoplasmic reticulum (ER), a network of tubes that build, package and transport proteins.

They named this mechanism translation-independent ER association (TiERA) and found that some mRNAs possess specific sequences and structures that determine their potential to undergo APA and ultimately associate with the ER.

“When mRNAs leave the nucleus and move to the cytoplasm, they need to be properly directed to reach the appropriate site of protein translation,” said Tian. “The cytoplasm is a huge space for an RNA molecule: For comparison, imagine entering a baseball stadium and needing directions to reach your seat.”

The team found that mRNAs with higher TiERA tend to encode for signaling proteins,which help cells communicate with each other by sending, receiving and processing signals in response to changes in the environment.

They propose that APA renders this process more efficient by anchoring certain mRNA isoforms with the ER in specific cellular locations where important signaling events happen.

Co-authors: Larry C. Cheng (co-first author) from The Wistar Institute; Dinghai Zheng and Aysegul Guvenek from Rutgers University; Qiang Zhang and Hong Cheng from Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, China.

Work supported by: National Institutes of Health (NIH) grants R01 GM129069 and T32 GM008339, and a Rutgers Presidential Fellowship Award. Additional support was provided by The Pew Charitable Trusts. Support for The Wistar Institute facilities was provided by Cancer Center Support Grant P30 CA010815.

Publication information: Alternative 3’UTRs play a widespread role in translation-independent mRNA association with endoplasmic reticulum, Cell Reports (2021). Online publication.

###

Melanoma Researchers Gathered at Wistar to Discuss Disease Progression and Therapy Resistance

Written by The Wistar Institute on June 29, 2021. Posted in Featured News.

Dedicated to the memory of melanoma research champions Dr. Shyam Somasundaram, Wistar scientist, and Eleanor Murdoch, melanoma advocate and mother of Noreen and Kate O’Neill, this year’s Symposium brought together international experts in basic and translational research to share their latest advances to understand disease progression and therapy resistance.

Both targeted therapies and immunotherapy have brought transformative improvements for melanoma treatment, increasing the average life expectancy for some patients with advanced disease from a matter of months to a matter years.

“Despite the substantial advances, we’ve reached a plateau in our ability to overcome therapy resistance and further improve patient survival,” said Dr. Keith Flaherty, director of Clinical Research at the Massachusetts General Hospital Cancer Center.

Researchers are focused on addressing resistance as a way to increase the fraction of patients who respond to these therapies and to fight tumors that come back after an initial response.

Targeted therapies work by blocking specific molecular targets that support the growth, progression, and spread of cancer. Scientists have identified two major ways melanoma cells evade these therapies. One involves reactivating the specific mechanism that is being blocked, for example by making more gene copies to produce more of a certain protein. Another trick is for cells to change their identity by switching on and off a set of genes that define their functions and behavior, so that they no longer need the protein targeted by the therapy.

New approaches aim to find vulnerabilities that can be exploited to kill melanoma cells after they’ve re-programmed themselves to resist therapy.

Dr. Thomas Graeber, professor and director of the Metabolomics Center at the University of California, Los Angeles, is studying drugs that cause a unique type of iron-dependent cell death called ferroptosis as a tool to enhance response to targeted therapies and immunotherapy.

Success of immunotherapy depends on the ability of our immune system to recognize and react to proteins that are specifically produced by melanoma cells as a result of genetic mutations and other mechanisms. These proteins, known as neoantigens, are critical because they flag tumor cells as dangerous or unwanted. Dr. Yardena Samuels, associate professor of Molecular & Cell Biology and the Knell Family Professor at the Weizmann Institute of Science in Israel, is applying high-throughput approaches to identify neoantigens that could be used to create cancer vaccines and other immunotherapies.

Epidemiologist Marianne Berwick, distinguished professor and associate director of Cancer Population Sciences at the University of New Mexico, leads an international team of investigators who have built a large collection of melanoma samples from patients in the U.S., Australia and Spain to identify new biomarkers that can inform better therapeutic approaches.

Melanomas are naturally heterogeneous tumors, with different subpopulations of cells that differ in aggressiveness and response to therapy. This heterogeneity is observed between patients and even within the same patient and represents an obstacle for immunotherapy success.

Medical oncologist Jedd Wolchok, chief of the Melanoma and Immunotherapeutics Service and the Lloyd J. Old Chair for Clinical Investigation at Memorial Sloan Kettering Cancer Center, and his team are investigating ways to potentiate immunotherapy approaches to overcome heterogeneity and kill resistant cells.

Dr. Wolchok has been at the forefront of cancer immunotherapy both as a research scientist exploring innovative strategies in laboratory models and as a principal investigator in many pivotal clinical trials. He recently led a global phase 3 trial to identify the most effective combination checkpoint blockade therapy for melanoma, which had a 58% response rate.

“We’ve reached an average survival of 72.1 months, which is a huge improvement compared to what we could do before immunotherapy and targeted therapy,” said Dr. Wolchok. “But immunotherapy doesn’t work for everybody, and has a high frequency of toxicity, so we still have work to do to sharpen the risk/benefit ratio and help the nearly half of patients who don’t benefit from this combination therapy.”

He thinks that some patients might need an additional boost with different types of immunotherapy. His lab is studying engineered T cells that are modified in the lab to attack melanoma cells presenting a certain protein. They have found that these T cells can also kill tumor populations that don’t express that same antigen, an effect called bystander tumor killing, with the help of other immune cells called neutrophils.

In closing the event, Dr. Jessie Villanueva, associate professor at The Wistar Institute Cancer Center who leads a productive research team working on therapy resistance and hard-to-treat melanomas, invited everyone back for the fifth edition.

All the speakers look forward to next year’s Symposium to be held in person at the Institute.