Author: The Wistar Institute

The Wistar Institute Receives Transformative National Science Foundation Grant to Expand and Accelerate STEM Training Program

Written by The Wistar Institute on May 11, 2021. Posted in Press Releases.

PHILADELPHIA — (May 11, 2021) — The Wistar Institute received a $599,969 grant from the National Science Foundation (NSF) to scale up its Biomedical Technician Training (BTT) Program to train more students in a condensed timeline with a direct path to employment.

“If there is one thing that we learned from the tragedy of the COVID-19 pandemic, it is that we need more science, more scientists and more innovators in STEM careers and the life sciences. Like we always say at Wistar, science is the answer, and we are absolutely delighted that the NSF has recognized our decades-long impact and track record of excellence in these areas,” said Dario Altieri, M.D., president and CEO, director of the Cancer Center, and the Robert and Penny Fox Distinguished Professor of The Wistar Institute. “The new NSF award will be truly transformative for supporting innovation in education and training, fulfilling our goal of creating a unique framework that merges teaching and job creation in the life sciences in a single, seamless continuum in our region and beyond.”

Since 2000 The Wistar Institute’s BTT Program, a two-summer, hands-on, mentored technician training program, has prepared Community College of Philadelphia (CCP) students for positions in academic and biotechnology laboratories. This NSF grant will support a substantial expansion of this program with innovative curricula and the inclusion of additional community colleges.

During the new NSF-supported program, named Expansion, Curriculum Evolution, and Enhancement during BioTechnician Training (ExCEEd BTT), students will follow an accelerated, one-summer pre-apprenticeship training including a hands-on orientation at Wistar and two full-time, mentored laboratory experiences in academia and industry. Program graduates will be prepared for immediate employment as laboratory technicians and may also continue training through Wistar’s registered Biomedical Research Technician (BRT) Apprenticeship.

The BTT and BRT Programs will continue to provide training and research experiences not typically available to associate degree students, a segment of the workforce that is indispensable to support the success of an ever-expanding biotechnology sector. ExCEEd BTT will allow Wistar to continue to train a diverse and underrepresented student population not generally included in life sciences research.

“The most effective way to increase diversity in research is to provide training opportunities for everyone and to support students from underrepresented groups to meet their full potential and access career paths in the life sciences,” said Kristy Shuda McGuire, Ph.D., Wistar associate dean of biomedical studies and principal investigator on the grant. “For 20 years, our educational programs have moved in that direction, and we are thrilled to be able to enhance our training thanks to NSF support. We hope this program will also serve as a model for other community colleges and scientific research partners.”

ExCEEd BTT has three primary goals: expand the program to recruit more students from additional community college partners, while developing collaborations that make ExCEEd BTT credit-bearing; develop a project-based curriculum specifically tailored to teach biotechnology research skills and engage students from underrepresented groups; and enhance the existing two-summer program as a one-summer pre-apprenticeship training experience with full-time internships in both academic and industry labs.

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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.org.

Wistar Expands International Training of the Next Generation of Scientists With the University of Bologna

Written by The Wistar Institute on April 27, 2021. Posted in Press Releases.

PHILADELPHIA — (April 27, 2021) — The Wistar Institute and the University of Bologna (Unibo) in Italy have established the Wistar-Unibo Ph.D. Exchange Program in Cell and Molecular Biology to bring Unibo graduate students to Wistar for their three-year Ph.D. training.

The program fosters scientific and intellectual exchange in research and education between Italy and the United States, and is aligned with Wistar’s commitment to expand and strengthen its network of collaborations for the research and training of junior scientists in the U.S. and beyond.

“Science is a global endeavor, so it is critical to join forces and exchange ideas and perspectives across international borders to create impactful research opportunities, and develop these top students into science trailblazers,” said Dario C. Altieri, M.D., Wistar president and CEO, director of the Institute’s Cancer Center and the Robert & Penny Fox Distinguished Professor. “We believe in the importance of training future scientific leaders, and we are excited to partner with Unibo, a dynamic institution with a long and storied history of international exchanges.”

The Wistar Institute is an international leader in fundamental biomedical research and technological innovation with special expertise in cancer and immunology research and vaccine development.

Unibo, the oldest university in the western world, is one of the largest institutions of undergraduate and graduate education in Italy and ranks within the world’s top 100 institutions for life sciences and medicine. With more than 87,000 students, Unibo encompasses five campuses, five schools and 10 research and training centers.

Students enrolled in the Wistar-Unibo Ph.D. Exchange Program are matched with a Wistar laboratory based on their research interests and present their progress every year at a workshop with fellow Ph.D. students in Italy.

The first three students in the Program have recently started their training in the Cancer Center laboratories of Alessandro Gardini, Ph.D., Italo Tempera, Ph.D., and Rugang Zhang, Ph.D.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, 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.org.

Latest Wistar Discoveries: Fine-tuning Vaccine Delivery in Preclinical Models to Advance MERS DNA Vaccine Candidate and Discovering New Targets for Cancer Therapy

Written by The Wistar Institute on April 27, 2021. Posted in Featured News.

A team of Wistar scientists led by Dr. David Weiner, Wistar executive vice president, director of the Vaccine & Immunotherapy Center and W.W. Smith Charitable Trust Professor in Cancer Research, and Dr. Ami Patel, Caspar Wistar Fellow, and collaborators have developed a synthetic DNA vaccine candidate for Middle East respiratory syndrome coronavirus (MERS-CoV).

A vaccine candidate based on their research was shown to be safe and tolerable in a recently completed human phase 1 study with a three-dose intramuscular injection regimen and is currently in phase 1/2a trial.

Our scientists continue to expand the preclinical studies of the vaccine in support of its clinical development. They have now tested intradermal delivery using a shortened two-dose immunization schedule in non-human primates (NHP).

“Low-dose delivery and shortened regimes are crucial to rapidly induce protective immunity, particularly during emerging outbreaks, as the current SARS-CoV-2 pandemic has emphasized,” said Weiner.

In a paper published in the journal JCI Insight, he and colleagues reported that low-dose intradermal administration induces potent immunity and protects from virus challenge. The low-dose regimen with intradermal delivery was more impactful in controlling disease and symptoms than the higher dose given intramuscularly.

“Intradermal delivery of synthetic DNA vaccines has significant advantages for rapid clinical development. It can be dose sparing and has higher tolerability in people compared with intramuscular injection,” said Patel.

Their experience developing this MERS vaccine candidate helped the team advance a COVID-19 vaccine through clinical trials in a short time.

Vaccine candidates that are simple to deliver, well tolerated, and can be readily deployed in resource-limited settings will be important to achieve control of infection for coronaviruses and other emerging infectious diseases.

The lab of Dr. Rugang Zhang, deputy director of The Wistar Institute Cancer Center, Christopher M. Davis Professor and leader of the Immunology, Microenvironment & Metastasis Program, studies the process of cellular senescence and the changes in gene expression that accompany it.

Cellular senescence is a stable state of growth arrest in which cells stop dividing but remain viable and produce an array of inflammatory molecules collectively defined as senescence-associated secretory phenotype (SASP). These molecules account for the complex crosstalk between senescent cells and neighboring cells and the effect of cellular senescence in various physiological processes like aging and diseases like cancer.

Although senescence is regarded as a powerful barrier for tumor development, the SASP plays a role during tumor development promoting the growth of established tumors.

In a new study published in Nature Cell Biology, Zhang and colleagues pointed out a new mechanism that allows cells to turn on a set of genes encoding for the SASP molecules.

“This mechanism may potentially be targeted to stop the tumor-promoting aspect of senescence while preserving its antitumor function,” said Zhang.

The team focused on two proteins called METTL3 and METTL14 that are known for other molecular functions and found that these proteins moonlight as regulators of gene expression that help turn on SASP genes.

“Although we focused on senescence, we envision that this function of METTL3 and METTL14 may be involved in many other biological processes beyond our current study,” said Zhang.

Wistar and Leiden University Medical Center Engage in Collaborative Seminars

Written by The Wistar Institute on April 27, 2021. Posted in Featured News.

Two institutions forge a valuable international collaboration based on training and emerging research alignment.

Wistar and Leiden University Medical Center (LUMC) in the Netherlands have started building a scientific bridge by connecting virtually to exchange information on their research programs, scientific goals, and core resources.

The Wistar-Schoemaker International Postdoctoral Fellowship will not only bring LUMC graduates to Wistar labs for their postdoctoral training hopefully this fall, but it also created a connection to establish new scientific collaborations between the two institutions that share several areas of research interest.

In a series of three virtual seminars, scientific leadership and researchers from Wistar and LUMC came together to present their ongoing projects and highlight potential collaborative avenues. In the first seminar, Drs. Dario Altieri, Wistar president and CEO, and Pancras Hogendoorn, dean of LUMC, opened the series presenting an overview of both institutes.

For the second seminar, Wistar and LUMC cancer researchers discussed their respective projects, while for the third seminar it was the turn of vaccine and immunology researchers from both institutions to delve deeper into vaccine and immunotherapy research, including their COVID-19 efforts.

Wistar is excited to see how collaborative beginnings and new areas of scientific interest take shape and drive exciting research and growth for both student-scientists and scientific leaders.

Dr. Ebony Gary Received Awards from American Association of Immunologists and American Society of Gene & Cell Therapy

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

Congratulations to Ebony Gary, Ph.D., postdoctoral fellow from the Weiner lab, for receiving the 2021 AAI Trainee Abstract Award from the American Association of Immunology and having her abstract selected for presentation at Virtual Immunology 2021. Gary was also awarded an Underrepresented Minority Travel Award from the American Society of Gene & Cell Therapy for the Society’s annual meeting.

At these prestigious conferences, Gary will present her research focused on developing adjuvants to enhance the response to SARS-CoV-2 vaccination in the elderly population, which is the most at risk of severe complications. The lab focuses on the use of biological adjuvants — molecules naturally involved in enhancing the magnitude and breadth of immune responses.

Gary obtained her M.S. and Ph.D. in microbiology and immunology studying DNA vaccines for HIV. When she joined the Weiner lab she expanded her research interest to include developing DNA vaccines for pediatric brain cancer.

Drs. David Weiner and Ami Patel working at a hood in the lab

Low-dose Administration of MERS DNA Vaccine Candidate Induces Potent Immunity and Protects From Virus Challenge in Preclinical Models

Written by The Wistar Institute on April 22, 2021. Posted in Press Releases.

PHILADELPHIA — (April 22, 2021) — A synthetic DNA vaccine candidate for Middle East respiratory syndrome coronavirus (MERS-CoV) developed at The Wistar Institute induced potent immune responses and afforded protective efficacy in non-human primate (NHP) models when given intradermally in abbreviated, low-dose immunization regimen. A similar vaccine candidate was previously shown to be safe and tolerable with a three-dose intramuscular injection regimen in a recently completed human phase 1 study and is currently in expanded studies of phase 1/2a trial. New results were published today in JCI Insight.

“While several vaccine products are being advanced against MERS and other coronaviruses, low-dose delivery and shortened regimes are crucial to rapidly induce protective immunity, particularly during emerging outbreaks, as the current SARS-CoV-2 pandemic has emphasized,” said David B. Weiner, Ph.D., Wistar executive vice president, director of the Vaccine & Immunotherapy Center (VIC) and W.W. Smith Charitable Trust Professor in Cancer Research, who led the study.

Researchers evaluated the immunogenicity and protective efficacy of their MERS synthetic vaccine when delivered intradermally using a shortened two-dose immunization schedule compared with intramuscular delivery of higher doses in NHP.

“Given that human efficacy trials for MERS vaccines may be challenging due to the low number of yearly cases, animal models such as our NHP model are valuable as a bridge with human data coming from early-phase clinical trials,” said Weiner.

In this study, Weiner and team report robust antibody neutralizing antibodies and cellular immune responses in all conditions tested. A rigorous virus challenge experiment showed that all vaccination groups were protected against MERS-CoV compared to unvaccinated control animals. However, the low-dose regimen with intradermal delivery was more impactful in controlling disease and symptoms than the higher dose delivered intramuscularly in NHP models.

“To our knowledge, this is the first demonstration of protection with an intradermally delivered coronavirus vaccine,” said Ami Patel, Ph.D., Caspar Wistar Fellow at the Vaccine & Immunotherapy Center and one of the lead authors of the paper. “Intradermal delivery of synthetic DNA vaccines has significant advantages for rapid clinical development. It can be dose sparing and has higher tolerability in people compared with intramuscular injection. The positive results of this study are important not only for the advancement of this MERS vaccine but also for development of other vaccines.”

“Our team is also advancing a COVID-19 vaccine through clinical trials, and we were able to do so in a very short time thanks to our previous experience developing the MERS vaccine,” added Weiner.

Importantly, no evidence of adverse effects on the lungs was observed in any of the dosing groups compared to unimmunized control animals. Through the assessment of a large panel of blood cytokines, researchers showed significant decrease in all mediators of inflammation, which further suggests the vaccine prevents the destructive inflammation induced by coronaviruses.

“In the past twenty years, three new coronaviruses have emerged and caused human outbreaks. The current SARS-CoV-2 pandemic has further emphasized the importance of rapid infection control for coronaviruses and other emerging infectious diseases,” said Emma L. Reuschel, Ph.D., a staff scientist in the Weiner lab and co-first author on the study. “Vaccine candidates that are simple to deliver, well tolerated, and can be readily deployed in resource-limited settings will be important to achieve control of infection.”

Co-authors: Ziyang Xu, Faraz I. Zaidi, Kevin Y. Kim, Regina Stoltz, and Kar Muthumani from The Wistar Institute; Dana P. Scott, Friederike Feldmann, Tina Thomas, Rebecca Rosenke, Dan Long, Jamie Lovaglio, Patrick W. Hanley, and Greg Saturday from National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT; Janess Mendoza, Stephanie Ramos, Laurent Humeau, and Kate E. Broderick from INOVIO Pharmaceuticals, Inc.

Work supported by: Funding from the Intramural Research Program, National Institutes of Allergy and Infectious Diseases, and the Coalition for Epidemic Preparedness Innovations (CEPI).

Publication information: Intradermal delivery of a synthetic DNA vaccine protects macaques from Middle East respiratory syndrome coronavirus, JCI Insight (2021). Online publication.

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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 Scientists Discover New Mechanism Through Which Senescent Cells Turn On Genes That Encode for Secreted Tumor-regulating Factors

Written by The Wistar Institute on April 1, 2021. Posted in Press Releases.

PHILADELPHIA — (April 1, 2021) — Scientists at The Wistar Institute identified a new mechanism of transcriptional control of cellular senescence that drives the release of inflammatory molecules that influence tumor development through altering the surrounding microenvironment. The study, published in Nature Cell Biology, reports that methyltransferase-like 3 (METTL3) and 14 (METTL14) proteins moonlight as transcriptional regulators that allow for establishment of the senescence-associated secretory phenotype (SASP).

Cellular senescence is a stable state of growth arrest in which cells stop dividing but remain viable and produce an array of inflammatory and growth-promoting molecules collectively defined as SASP. These molecules account for the complex crosstalk between senescent cells and neighboring cells and the effect of cellular senescence in various physiological processes and diseases. Although senescence is regarded as a potent barrier for tumor development, the SASP plays a stage-dependent role during tumor development, mediating the clearance of premalignant lesions during initiation and promoting the growth of established tumors.

“Senescent cells undergo widespread changes in gene expression needed to adapt their phenotype and functions,” said Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, Christopher M. Davis Professor and leader of the Immunology, Microenvironment & Metastasis Program. “We pointed out a new mechanism that allows cells to turn on a set of genes encoding for the SASP molecules and may potentially be targeted to inhibit this aspect of senescence while preserving its antitumor function.”

Zhang, who is senior author on the study, and his team focused on METTL3 and METTL14, proteins known for chemically modifying messenger RNA to regulate its function. They found a new role of these proteins in senescence and regulation of gene expression that is independent of their RNA-modifying function.

Depleting cells of METTL3 and METTL14, researchers observed reduced expression of SASP genes, such as inflammatory cytokines, but no effect on cell cycle arrest or other markers of senescence, indicating that decrease in SASP is not an indirect consequence of overall senescence inhibition.

“Our results indicate that METTL3 and METTL14 promote expression of SASP genes, in accordance with other studies that revealed an oncogenic role for these two proteins,” said Pingyu Liu, Ph.D., first author of the study and a staff scientist in the Zhang Lab.

The team further analyzed the association of METTL3 and METTL14 with DNA, comparing senescent and control cells. While the two proteins are found together on DNA in control cells, in senescent cells they have different distribution patterns, whereby METTL3 tends to sit upstream of SASP genes, near the transcription start site, while METTL14 binds away from gene bodies, on regulatory elements called enhancers.

Researchers demonstrated that through this positioning pattern and interacting with each other, METTL3 and METTL14 bring closer together two DNA sequences that in non-senescent cells are distant, allowing the formation of promoter-enhancer chromatin loops. As a consequence, expression of the SASP genes is turned on.

“Although we focused on senescence, we envision that the transcription-regulating function of METTL3 and METTL14 may be involved in many other biological processes beyond our current study,” concluded Zhang.

Co-authors: Jianhuang Lin, Takeshi Fukumoto, Timothy Nacarelli, Xue Hao, and Andrew V. Kossenkov from The Wistar Institute; Fuming Li and M. Celeste Simon from University of Pennsylvania.

Work supported by: National Institutes of Health (NIH) grants R01CA160331, R01CA163377, R01CA202919, R01CA239128, R01CA243142, P01AG031862 to R.Z., P50CA228991, and R50CA211199; U.S. Department of Defense grants OC180109 and OC190181. Additional support was provided by The Honorable Tina Brozman Foundation for Ovarian Cancer Research and The Tina Brozman Ovarian Cancer Research Consortium 2.0; and Ovarian Cancer Research Alliance (Collaborative Research Development Grant #596552 and Ann and Sol Schreiber Mentored Investigator Award #649658). Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.

Publication information: m6A-independent genome-wide METTL3 and METTL14 redistribution drives senescence-associated secretory phenotype, Nature Cell Biology, 2021. Online publication.

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Richard M. Horowitz Appointed Chair of The Wistar Institute’s Board of Trustees

Written by The Wistar Institute on March 23, 2021. Posted in Press Releases.

PHILADELPHIA — (March 23, 2021) — The Wistar Institute, a global leader in biomedical research in cancer, immunology and infectious disease, is pleased to announce the appointment of Richard M. Horowitz as chair of its Board of Trustees. Horowitz, who serves as president and CEO of RAF Industries, Inc., has been a member of Wistar’s Board since 2002 and vice-chair since 2012. Horowitz succeeds Helen P. Pudlin, Esq., who has chaired the board since 2012 and will continue to serve as an active member.

“I’m excited by what the future holds at Wistar and deeply honored to be assuming this role at a critical moment in the history of the Institution,” said Horowitz. “Wistar has been an engine of important medical discovery for over a century and it’s poised now for even greater scientific leadership — not just in groundbreaking cancer research, but also in the new frontier of pandemic preparedness, where Wistar is exceptionally well equipped to advance medical science. Helen’s leadership has been inspiring, and I look forward to working with everyone at Wistar to realize the vision.”

“It’s been a great privilege and a source of enormous personal fulfillment to serve as chair of Wistar’s Board of Trustees,” said Pudlin, retired executive vice president and general counsel of the PNC Financial Services Group. “I’m incredibly proud of what Wistar has accomplished as a discovery science institution during the past eight years, and its testament to the exceptional talents of our scientists, the vision of our executive leadership, and the remarkable commitment of my colleagues on the board. This recent era has seen the construction of the Fox Tower, which created new space and facilities for some of the best and brightest researchers in the world and has enabled unprecedented collaborations in HIV, cancer research, and infectious disease. Not only are we contributing to the advancement of scientific initiatives on a global scale, we are playing a key role in the scientific and educational vitality of our region, whose reputation as a biomedical science hub is growing rapidly.”

“Helen’s dedication to the mission of The Wistar Institute during these transformative times has been unwavering, and I am deeply grateful for her passion and guidance,” said Dario C. Altieri, M.D., president and CEO, Cancer Center director, and the Robert and Penny Fox Distinguished Professor at The Wistar Institute. “Her leadership and vision have been instrumental in helping the Institute achieve ever higher levels of prominence in the worldwide biomedical research community. Wistar has always been focused on achieving global impact through bold, innovative research ideas, and Helen has been an incredibly effective champion of that mission. Wistar is in a transformative period. With Rick’s Board leadership, I’m confident we can maintain a level of momentum that’s unprecedented in our 130-year history.”

“Wistar is an institution that has always punched above its weight, and it’s also one of the most exciting places in the world of biomedical science to be right now. So much is happening here. And there is so much important work to be done. It’s really thrilling to be part of it,” said Horowitz.

Currently, Horowitz also serves as Netter Center National Advisory Board member and member of the Board of Advisors of the University of Pennsylvania’s School of Arts and Sciences, as well as board member of the Children’s Crisis Treatment Center and National Constitution Center.

Sue Dillon, Ph.D., who is co-founder and CEO of Aro Biotherapeutics, has been elected to serve as the new vice-chair. Dillon was previously global therapeutic area head, Immunology, at Janssen Research & Development, a pharmaceutical company of Johnson & Johnson.

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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 US, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances advance from the laboratory to the clinic as quickly as possible. wistar.org.

Dr. Katelyn Miller Awarded American Cancer Society Fellowship

Written by The Wistar Institute on March 22, 2021. Posted in Featured News.

Katelyn Miller, Ph.D., postdoctoral fellow in the Wistar lab of Dr. Zach Schug, is the recipient of the prized Rena and Victor Damone Postdoctoral Fellowship in Cancer Research from the American Cancer Society (ACS). Awarded through the Extramural Discovery Sciences program, which is the research arm of the ACS, this two-year fellowship funds high-impact cancer research by the most promising, early-career scientists doing innovative work in the field.

Dr. Miller will study the dietary distinctions of cancer cells and how they utilize the nutrients in food very differently from normal healthy tissues.

“We find that many breast tumors have an appetite for a nutrient called acetate and use it to help them to grow, become more aggressive and resist treatment,” said Miller. “Indeed, when we block the ability of breast cancer cells to use acetate, we stop their growth and make them more susceptible to attack by our own immune system. We believe that targeting acetate in combination with immunotherapy will greatly improve responses to treatment for breast cancer patients, but also in any cancer that relies on acetate. We hope to then develop therapies that specifically kill the cancer cells.”

The Philadelphia region has a dynamic research scene that has greatly benefitted from the critical support of the ACS, the largest private funder of cancer research outside of the federal government. For more than seven decades the ACS has buoyed the careers of the most promising and productive scientists.

“I am truly grateful to have been awarded the American Cancer Society Rena and Victor Damone Postdoctoral Fellowship,” said Miller. “It will allow me to further my research aimed at understanding how changes to a cancer cell’s diet impact patient responses to therapy. The funds and mentoring support provided will ultimately allow for a better understanding of the metabolic changes in breast cancer cells leading to targeted therapies and improved patient outcomes.”

Katelyn Miller, Ph.D., is supported by an American Cancer Society – Rena and Victor Damone Postdoctoral Fellowship in Cancer Research, PF-20-125-01-CCG.

RNA Editing Protein ADAR1 Protects Telomeres and Supports Proliferation in Cancer Cells

Written by The Wistar Institute on March 12, 2021. Posted in Press Releases.

PHILADELPHIA — (March 12, 2021) — Scientists at The Wistar Institute identified a new function of ADAR1, a protein responsible for RNA editing, discovering that the ADAR1p110 isoform regulates genome stability at chromosome ends and is required for continued proliferation of cancer cells. These findings, reported in Nature Communications, reveal an additional oncogenic function of ADAR1 and reaffirm its potential as a therapeutic target in cancer.

The lab of Kazuko Nishikura, Ph.D., professor in the Gene Expression & Regulation Program of The Wistar Institute Cancer Center, was one of the first to discover ADAR1 in mammalian cells and to characterize the process of RNA editing and its multiple functions in the cell.

Similar to changing one or more letters in a written word, RNA editing allows cells to make discrete modifications to single nucleotides within an RNA molecule. This process can affect RNA metabolism and how it is translated into proteins and has implications for neurological and developmental disorders and antitumor immunity.

There are two forms of the ADAR1 protein, ADAR1p150 and ADAR1p110. While the RNA editing role of the former, located in the cytoplasm, has been extensively characterized, the function of the nuclear ADAR1p110 isoform remained elusive.

“We discovered that in the nucleus, ADAR1p110 oversees a similar mechanism to ADAR1p150, the better-known cytoplasmic variant, but the editing process in this case targets particular nucleic acid structures called R-loops when formed at the chromosome ends,” said Nishikura. “Through this function, ADAR1p110 seems to be essential for cancer cell proliferation.”

R-loops form during gene transcription when, instead of dissociating from its template DNA strand, the newly synthesized RNA remains attached to it, leading to a stable DNA/RNA hybrid. While these structures can be beneficial for transcriptional regulation in certain conditions, accumulation of R-loops can cause DNA damage, chromosome rearrangements and genomic instability and is linked to neurological disorders and cancer.

Nishikura and colleagues found that ADAR1p110 helps the cells resolve R-loops and prevent their accumulation by editing both the DNA and the RNA strands involved in the structure and facilitating degradation of the RNA strand by the RNase H2 enzyme.

Notably, researchers found that ADAR1p110 depletion results in accumulation of R-loops at the chromosome ends, indicating that ADAR1p110 acts on R-loops formed in the telomeric regions and is required to preserve telomere stability.

Telomeres serve as an internal clock that tells normal cells when it’s time to stop proliferating. Just like the plastic coating on the tips of shoelaces, telomeres protect chromosome ends from the loss of genetic material at each cell division, by their progressive shortening eventually triggers growth arrest or cell death.

Cancer cells bypass this mechanism to become immortal. Researchers found that ADAR1p110 depletion leads to extensive telomeric DNA damage and arrested proliferation specifically in cancer cells.

“It has recently been suggested ADAR1 inhibitors could potentiate tumor response to immunotherapy by interfering with certain cytoplasmic ADAR1p150 functions,” said Nishikura. “Based on our findings on the role of nuclear ADAR1p110 in maintaining telomere stability in cancer cells, we predict that ADAR1 inhibitors would be very effective anticancer therapeutics by interfering with two different and independent pro-oncogenic ADAR1functions exerted by the two isoforms.”

Co-authors: Yusuke Shiromoto*, Masayuki Sakurai*, Moeko Minakuchi*, and Kentaro Ariyoshi from The Wistar Institute. *Co-first authors.

Work supported by: National Institutes of Health (NIH) grants GM040536, CA175058, and GM130716; additional support was provided by the Emerson Collective, the Japan Society for the Promotion of Science (JSPS), and the Uehara Memorial Foundation. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.

Publication information: ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells, Nature Communications, 2021. Online publication.

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