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Author: The Wistar Institute

First In-Person Jonathan Lax Memorial Award Lecture Since 2019 Brings Scientists, Community Together at The Wistar Institute

Philadelphia—For the first time since 2019, The Wistar Institute opened its doors to host, in person, the 27th annual Jonathan Lax Memorial Award Lecture, which featured Deborah Persaud, M.D., Professor of Pediatrics at the Johns Hopkins School of Medicine as the keynote speaker. The event brought together researchers and members of the AIDS community from across the country; attendees also had the opportunity to join the first-ever hybrid Lax Lecture virtually.

Dr. Deborah Persaud, in delivering the first Lax Lecture to focus on pediatric HIV/AIDS, spoke of the importance of swift intervention for testing and treating peripartum (that is, transmitted during birth) and pediatric HIV/AIDS.

Her work, she explained to the audience of laypersons and scientific experts alike, has demonstrated that early treatment with antiretroviral therapy can deliver much better quality-of-life outcomes (including, in rare cases, remission) compared with later treatment for pediatric patients living with HIV. Dr. Persaud defined early treatment as two to three months of age, and while this early intervention approach offers great promise, Persaud said, it also presents difficult logistical challenges:

“Most infants are tested around six weeks of age, and that’s why it takes two to three months to actually start antiretroviral treatment. We need to move our testing algorithm down so we can identify children earlier.”

The Jonathan Lax Memorial Award Lecture, in addition to sharing the research progress made on HIV/AIDS with the public, also honors the legacy of its namesake, Jonathan Lax. Philadelphia FIGHT CEO Jane Shull remarked, “Jonathan Lax was an extraordinary individual who, even while living through the darkest days of the AIDS epidemic, knew the importance of fighting for treatment — of fighting for a cure.”

Luis J. Montaner, D.V.M., D.Phil., Herbert Kean, M.D., Family Professor, leader of the HIV Research Program at The Wistar Institute and co-principal investigator of the BEAT-HIV Delaney Collaboratory (beat-hiv.org), presented Dr. Persaud with the Jonathan Lax Memorial Award for her years of work researching HIV/AIDS with a dedication to children living with HIV/AIDS.

“I’m very privileged to have received this award, and I’m standing here because of the commitment of many, many professional researchers, clinical trial participants, parents and children. So I’m representing the pediatric community as a group, and I want to offer thanks to Jonathan Lax for his activism and advocacy for treatment for persons living with HIV,” said Persaud.

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The Wistar Institute, the first independent, nonprofit biomedical research institute in the United States, marshals the talents of an international team of outstanding scientists through a culture of biomedical collaboration and innovation. Wistar scientists are focused on solving some of the world’s most challenging and important problems in the field of cancer, infectious disease, and immunology. Wistar has been producing groundbreaking advances in world health for more than a century. Consistent with its legacy of leadership in biomedical research and a track record of life-saving contributions in immunology and cell biology, Wistar scientists’ early-stage discoveries shorten the path from bench to bedside. wistar.org.

Wistar Receives Brook J. Lenfest Foundation Awards Grant for Life Science Training Program

The Brook J. Lenfest Foundation has awarded a $25,000 grant to The Wistar Institute’s Biomedical Technical Training (BTT) Program. The grant will help further the BTT Program’s mission to provide education, training and mentorship to regional community college students to support the talent pipeline needs of Philadelphia’s robust life science sector.

A one-of-a-kind program, Wistar’s BTT Program has offered biomedical laboratory training designed to supplement college courses and offer real-world research experiences to students for more than 20 years. Originally developed in partnership with the Community College of Philadelphia, the Program has since expanded to include students from Montgomery County Community College and Bucks County Community College in Pennsylvania as well as Camden County College in NJ.

In its longstanding commitment to a diverse talent pipeline in the life sciences sector, Wistar continues to collaborate with educational program throughout the region. Their plans include working with even more colleges over the coming years, including Delaware County Community College next year.

“We are extremely grateful to The Brook J. Lenfest Foundation for their generous support of the BTT Program,” said Dr. Kristy Shuda McGuire, dean of Biomedical Studies at The Wistar Institute. “This grant will enable us to support even more community college students as they develop the skills and experience they need to obtain in-demand jobs in the region’s growing life science industry.”

Students who complete the BTT Program have the opportunity to further their training through the Fox Biomedical Research Technician Apprenticeship, the first registered, non-traditional apprenticeship in biomedical sciences in the country. Together, the programs give students access to highly specialized technical and professional skills that are critical to the life sciences, while providing a wage as they train.

This is the second grant from The Brook J. Lenfest Foundation in support of the BTT Program for community college students.

Small gene, big problem: Dr. Jessie Villanueva works to better understand how a small protein affects melanoma growth

Dr. Jessie Villanueva, associate professor, Molecular & Cellular Oncogenesis Program, and associate director for Diversity, Equity and Inclusion at The Wistar Institute, and her team are working to understand how certain melanoma tumors bypass treatment. Her goal? To discover a strategy that blocks melanoma’s critical pathways and contributes to the development of treatments for patients who have few therapeutic options.

Learn more about Dr. Villanueva’s work in a recent Philadelphia Business Journal feature.

Quality Science Pathway Apprenticeship Applications Due July 31

The Wistar Institute’s Quality Science Pathway Apprenticeship provides an accelerated pathway to careers in the Biotechnology and Pharmaceutical industries. Applications for 2023-2024 are due by July 31.

Participants complete three industry developed courses taught by industry subject matter experts from Greater Philadelphia’s life science companies. 

  • Global Regulatory Requirements of Quality 
  • Product Development and Validation 
  • Risk Failure Analysis

Each course will require 3-5 hours per week, including class-time and assignments, and will be offered as an online, evening class. Upon completion of the program, apprentices receive certification as a Certified Quality Science Professional (CQSP).

Additional details, along with an online application, can be found on the Quality Science Pathway Apprenticeship page

Wistar Honors Pediatric HIV Researcher in 27th Annual Jonathan Lax Memorial Award Lecture

PHILADELPHIA—(June 22, 2023)—The Wistar Institute hosts its 27th Jonathan Lax Memorial Lecture Thursday, June 29th at 5:30 pm EST. For the first time since 2019, the signature event will be hosted in-person at Wistar; it is also being streamed to ensure attendees have access to the memorial lecture. This year, guest speaker Deborah Persaud, M.D., professor of Pediatrics and interim director of Pediatric Infectious Diseases at the Johns Hopkins University School of Medicine, will speak about her research on mother-to-child HIV transmission, pediatric HIV pathogenesis and pediatric cure therapeutics.

Dr. Persaud also serves as the scientific chair of the HIV CURE Scientific Committee of the International Maternal, Pediatric Adolescent AIDS Clinical Trials (IMPACT) group and as a Program Director of the PAVE (Pediatric Adolescent Virus Elimination) Martin Delaney Collaborative. She spoke of being selected to deliver the lecture with gratitude: “It is quite an honor to receive the Jonathan Lax Memorial Award and deliver the 27th annual lecture, which is dedicated to pediatric HIV cure-directed research for the first time. Receiving this tribute to Mr. Lax’s memory, who was such a force in the Philadelphia HIV/AIDS community, is an exceptional distinction.”

“We’re truly excited to host Dr. Persaud this year,” said Wistar’s Luis J. Montaner, D.V.M., D.Phil., the Herbert Kean, M.D., Family Endowed Chair Professor, leader of the HIV Research Program at The Wistar Institute and co-principal investigator of the BEAT-HIV Delaney Collaboratory. “The fight for an HIV/AIDS cure is all-encompassing, and Dr. Persaud’s expertise in pediatric cure-directed HIV research will help the public understand a facet of HIV/AIDS cure research that isn’t often discussed.”

The Wistar Institute and Philadelphia FIGHT established the Jonathan Lax Memorial Award Lecture after Mr. Lax’s death to honor his legacy by bringing distinguished speakers to a lay audience. Previous speakers include luminaries in the HIV/AIDS field such as Nobel Laureate Françoise Barré-Sinoussi, Ph.D., Professor Emeritus at the Institut Pasteur; Mike McCune, M.D., Ph.D., head of the HIV Frontiers Initiative and Biotechnology Accelerator Program of the Bill & Melinda Gates Foundation; and Anthony S. Fauci, M.D., former Director of the National Institute of Allergy and Infectious Diseases.
The 2023 lecture is free and open to a global audience. Register here for in-person attendance and register here for virtual attendance.

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The Wistar Institute is the first independent, nonprofit biomedical research institute in the United States, marshals the talents of an international team of outstanding scientists through a culture of biomedical collaboration and innovation. Wistar scientists are focused on solving some of the world’s most challenging and important problems in the field of cancer, infectious disease, and immunology. Wistar has been producing groundbreaking advances in world health for more than a century. Consistent with its legacy of leadership in biomedical research and a track record of life-saving contributions in immunology and cell biology, Wistar scientists’ early-stage discoveries shorten the path from bench to bedside. www.wistar.org

BEAT-HIV Delaney Collaboratory is part of an international consortium of more than 80 top HIV researchers from academia, industry, government, and nonprofit sectors working toward an HIV cure. The Collaboratory is leading three advanced trials to define effective ways to combine immunotherapy regimes towards a cure. www.BEAT-HIV.org

Philadelphia FIGHT is a Federally Qualified Health Center (FQHC) offering HIV treatment and primary care to people living with HIV/AIDS and those at high risk, as well as community education and outreach programs on HIV, Hepatitis, and other topics impacting public health. During the COVID-19 pandemic, FIGHT has provided no barrier, walk-up COVID testing to over 19,000 people in low-income neighborhoods of Philadelphia and partnered with ten community-based organizations to bring COVID vaccines to communities. www.fight.org

Wistar Institute Study Gives New Insight into How Cancer Metastasizes to the Brain

PHILADELPHIA — (June 20, 2023) — When cancer that starts in the body metastasizes to the brain, it is almost always lethal, in part because so few treatment options exist. Now a new study by Wistar scientists published in Nature Communications shows that a type of brain cell called astrocytes plays an important role in promoting brain metastasis by recruiting a specific subpopulation of immune cells.

caplan canceThe finding could be a first step toward identifying potential targets for therapies to fight cancers that metastasize to the brain. This would fill a significant unmet need, said researcher Qing Chen, M.D., Ph.D., assistant professor, Immunology, Microenvironment & Metastasis Program, Ellen and Ronald Caplan Cancer Center at The Wistar Institute. because treatment options for brain metastasis have lagged behind, even as advances in other cancer therapies have made enormous strides, making those cancers much more treatable.

“It can be devastating for patients and their families, because they go through so much treatment, they survive the breast cancer, they all celebrate, and then it shows up in the brain,” leading to a terminal diagnosis, she said.

Several types of cancer are known for metastasizing to the brain, including breast, lung, carcinoma, and melanoma. One reason conventional treatments do not work on these cancers after they reach the brain is because the brain is such a different environment from the rest of the body, with unique brain cells (neuron and glia cells) providing different support to the metastatic cancer cells.

For the study, researchers wanted to better understand the cancer-brain interactions that trigger metastasis when cancer cells enter the brain. They focused on astrocytes, a type of star-shaped cell that helps form connections between neurons.

Using brain metastasis mouse models, researchers showed that when the astrocytes were exposed to cancer cells, they began to activate type I interferon pathways. Type I interferon, the cytokines associated with regulating inflammation, have been shown to have to anti-tumor effects. However, more and more evidence suggest controversial effects of type I IFN signaling in chronic inflammation and cancer.

“That was an exciting surprise,” Chen said, adding that it was the first time the type I interferon response had been implicated to promote brain metastasis.

They found that the interferon response was being activated at a low level but for a prolonged period of time. This could explain why a process that is normally associated with helping the immune system was actually causing harm by supporting tumor growth. Previous studies have found that low-level, chronic interferon response can cause negative health outcomes, she noted.

When they took a closer look, researchers found that the interferon signaling was activating production of a chemokine called CCL2, which in turn attracted harmful immune cells called monocytic myeloid cells. These cells promote tumor growth.

Researchers then studied mice that were genetically altered to abolish the type I interferon activation in astrocyte cells. They found that mice that were missing this pathway had fewer brain metastases.

“That shows the type I interferon response in astrocyte cells actually promotes metastasis,” Chen said.

She noted researchers found a similar result with both melanoma and breast cancer cells, showing that the process – and potential therapeutic targets – occur across different cancer types.

Chen hoped the findings encouraged more researchers to study the interactions that lead cancers to metastasize in the brain.

“It’s an urgent need to have more people pay attention to this problem, and hopefully we’ll have more basic researchers and clinicians participate in future studies, as well as more resources,” she said.

Next, Chen’s team is applying for a federal grant from the National Cancer Institute (NCI) for a follow up study to better understand the mechanism and timing of how astrocytes and the interferon response promote brain metastasis, with a goal of identifying the best therapeutic window for treating and stopping this process.

Co-authors: Wili Ma, Maria Cecilia Oliveira-Nunes, Andrew Kossenkov, and James Hayden of Wistar, Ke Xu of Boston University School of Medicine, Benjamin C. Reiner and Richard C. Crist of the University of Pennsylvania.

Work supported by: Susan G. Komen, V Foundation for Cancer Research, and the NIH/NCI.

Publication information: Type 1 interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment Nature Communications, 2023. Online publication.

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The Wistar Institute, the first independent, nonprofit biomedical research institute in the United States, marshals the talents of an international team of outstanding scientists through a culture of biomedical collaboration and innovation. Wistar scientists are focused on solving some of the world’s most challenging and important problems in the field of cancer, infectious disease, and immunology. Wistar has been producing groundbreaking advances in world health for more than a century. Consistent with its legacy of leadership in biomedical research and a track record of life-saving contributions in immunology and cell biology, Wistar scientists’ early-stage discoveries shorten the path from bench to bedside. wistar.org.

The Art and Science of Dr. Livio Azzoni

Dr. Livio Azzoni racks up 20+ miles a week running to and from work at The Wistar Institute. This senior staff scientist in the laboratory of Dr. Luis Montaner took up running 13 years ago because he was, “Growing, but in the wrong direction. [I] was growing in girth so I decided to do something, and it stuck.” What’s more intriguing is that Livio runs barefoot. He runs the Schuylkill River Trail from East Falls into West Philadelphia. He hops over glass shards and other treacherous street bits, running rain or shine, and stopping only when temperatures dip below 30 degrees. Though it is this scientist’s preferred running style he concedes it might not be for everyone.

“I must be very focused on where I step. I also practice cyclic breathing (for example, breathe in for four steps and out for four steps). I think this combination is very meditative—it’s yoga in motion: instead of holding a pose, you’re moving. It helps focus on experiencing the moment, so it’s sort of a mindfulness exercise,” said Livio.

For this immunologist moving the mind through heightened creativity and ability seems to be a running consequence.

Livio is a researcher in the Montaner HIV research lab. The lab is a BEAT-HIV Delaney Collaboratory with international impact and a finely tuned team of researchers conducting collaborative, cure-directed research in a transformational program nationally and internationally renowned. Beyond carrying out basic (foundational) research and translational research with an eye toward new drugs and therapies, lab members contribute to population studies and plan and execute state-of-the-science clinical trials. With links connecting local and global partners, the lab maintains strong ties with the local community, community partner organizations, federal HIV/AIDS organizations, major academic science groups, and advocacy groups. The goal is an HIV cure.

Wistar scientists are a high-achieving lot even outside the many lab research hours they spend. Livio is one of those high functioning, immensely creative individuals whose rigorous work life parallels a creative and unconventional private life—pursuing art through pottery and mindfulness through long distance running.

Livio’s path to science was extraordinary. His mother and father moved back to Torino, Italy, from the Democratic Republic of the Congo just before he was born. In high school he enjoyed biology and chemistry and interned at a local hospital. Since students were not allowed to work with patients, Livio interned in the hospital lab. It’s there he developed his clinical lab interest. Livio was the second person in his family to attend university. Next, he obtained his M.D. at the University of Torino and then went on to mandatory military service in the Italian Army. “My time in the Army was the only time I ever actually practiced as a doctor—to 2,000 fellow Army cadets,” said Livio.

Supported with money saved from his military service Livio volunteered at the Pathology Institute for the University of Torino which launched him to the Ph.D. program at the Cancer Institute at the University of Genoa under mentor-scientist-physician Dr. Manlio Ferrarini. From there Livio left for the U.S. and cut his teeth on basic immunology studying natural killer cells at the bench in the Wistar lab of the late Dr. Bice Perussia. He followed Dr. Perussia to the Jefferson Cancer Center, working in basic research for the next 10 years and eventually pursuing a certificate in Management from the Wharton School of Business at the University of Pennsylvania.

As his interest evolved to a more clinical focus, in 2000 Livio returned to Wistar joining the Montaner lab to run a clinical study in South Africa just six years after apartheid ended. He worked on multiple projects studying HIV pathogenesis, intermittent treatment and recovery outcomes of people living with HIV.

“This project focused on underserved populations. At the time, very little clinical research was being done in these people that could benefit them directly” said Livio. “Up to 2003, no antiretroviral treatment (ART) was available to the vast majority of HIV-infected individuals in South Africa. Our group worked closely with the doctors spearheading the effort to force the South African government to provide free ART treatment. Our study allowed many individuals who would not have qualified under the government rollout to obtain ART as recommended by the WHO guidelines”

South Africa was a country of contrasts. A modern healthcare delivery infrastructure was in place, but only accessible to White South Africans. When apartheid ended Black South Africans gained access to a modern but undersized healthcare system, which struggled to deliver access to millions of HIV-infected individuals (an estimated 5.3 million in 2002, according to UNAIDS). This was a uniquely productive time to be on the ground working with communities with healthcare access.

“Many people were living in poverty and treating people was a luxury, and obviously, HIV wasn’t the only disease and resources were limited,” said Livio. “Apartheid had kept Black and “Colored” South Africans segregated in all aspects of life, including healthcare. With the end of apartheid, all South Africans gained access to the formerly segregated modern healthcare facilities. It was a huge challenge on resources and infrastructure, but also an extremely rewarding time—a very fertile ground for research and for ideas.”

Twice a year Livio traveled to South Africa, but he also had projects running locally through Montaner lab connections to Philadelphia FIGHT, a nonprofit advocacy organization providing a myriad of health, social and education services to people living with HIV as well as the greater Philadelphia community.

Currently Livio works on several eclectic clinical research projects. “The study of pathology and human disease, if nothing else, gives you empathy,” said Livio. “Documenting the physiology of a normal body layered with studying pathology of that body, is where data comes in. The data collection and characterization of data for use includes a broad range of scientific interests, that complements my varied education.”

Though possessing an immunologist’s mindset when it comes to pathogenesis and disease outcomes, he has a deep interest in data sciences and creating data-driven approaches to analyze and illuminate particular results. The Montaner lab creates clinical studies and Livio works with colleagues to design what data to collect and how best to collect it. Working alongside Luis Montaner, he can “big picture” what needs to be collected, understands the scientific process and how to analyze the data.

Livio credits Luis’ foresight to invest in data for their clinical trial research. Their lab’s expertise has led to the creation of Wistar’s Biomedical Research Support Facility, which provides scientists with the infrastructure to support clinical trials including data collection, control, analysis, site and regulatory support. Livio spends 50 percent of his time running this core facility.

“You need to know the processes by which data are collected,” said Livio. “In clinical research there’s a very specific path to ensure that everybody is tested and everybody’s participation produces actionable data. Essentially, it’s designing the system that collects the data, collecting the data, cleaning the data, quality management, quality control, and then finally having usable data.”

Livio believes there is a misconception that one needs to be a genius to be a scientist—if he can do it anyone can. Being a scientist really means following the passions, interests and curiosities that we all have. Livio lives that belief, whether it’s studying management to improve his skills, or becoming an amateur potter who throws large vessels on the pottery wheel and hand builds remarkable creations. His broad and varied scientific career keeps life interesting and mirrors a vibrant personal life.

If data were life, Livio keeps his data diverse and the digital noise low. He says nothing is canonized because it’s all variable and it all depends on the operations you have running. He may be talking data, but he thinks it is a good life lesson as well.

View Flickr photo album here.

Noam Auslander, Ph.D.

Assistant Professor, Molecular and Cellular Oncogenesis Program, Ellen and Ronald Caplan Cancer Center

Auslander focuses on developing machine learning methods to understand genetic and infectious factors that drive cancer development and identify patterns that can improve cancer diagnosis and treatment.

Auslander earned her B.S. in computer science and biology from Tel Aviv University and continued her studies in Maryland, where she obtained a computer science Ph.D. from the University of Maryland with a combined fellowship at the National Cancer Institute. She received postdoctoral training at the National Center of Biotechnology Information (NCBI) and joined The Wistar Institute in 2021 as an assistant professor.

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The Auslander Lab

215-495-6937

nauslander@wistar.org

The Auslander Lab

In the past years, enormous growth in the quantity of biomedical data has been paralleled by advances in computational and deep learning techniques. These rapidly accumulating biomedical and clinical datasets have the potential to uncover unknown genetic drivers of cancer, carcinogenic infectious agents, and new treatment biomarkers. To achieve this potential, there is a need for improved and more interpretable computational strategies that can handle different types of biomedical data.

The Auslander laboratory develops advanced machine and deep learning methods to identify factors that drive cancer development and predict patients’ prognoses. We focus on the development of deep learning methods to identify new infectious agents in cancer, and the development of machine learning strategies that improve outcome prediction through biologically interpretable classifiers.

Staff
  • Postdoctoral Fellow

    Abdurrahman Elbasir, Ph.D.

  • Graduate Students

    Anastasia Lucas
    Andrew Patterson
    Julia C Malnak (Rotation student, UPenn-GCB)

  • Research Assistants

    McKenna Reale
    Bryant Duong

Staff
  • Postdoctoral Fellow

    Abdurrahman Elbasir, Ph.D.

  • Graduate Students

    Anastasia Lucas
    Andrew Patterson
    Julia C Malnak (Rotation student, UPenn-GCB)

  • Research Assistants

    McKenna Reale
    Bryant Duong

Research

Characterization of the Tumor Microbiome with Machine Learning

Detection of new tumor microbes can advance early diagnosis and cancer prevention strategies. Our lab develops machine learning and sequence analysis frameworks to characterize the landscape of microbes that underlie different cancer types and modulate patient outcomes in cancer.

Quantification of Gut Microbial Genes and Development of Fecal Biomarkers

The gut microbiome has immense potential for improving cancer clinical decision-making through non-invasive fecal biomarkers. Our lab develops methods that improve quantification of microbial genes to allow reliable fecal biomarkers for cancer.

New Virus Characterization and Detection of Pathogenic or Immunogenic Viral Sequences

The human virome is highly heterogenous with numerous uncharacterized members. Our lab develops integrative machine learning and sequences analysis methods to identify new viruses, viral genes, or genomic regions that are associated with disease risk, severity, and immune responses.

Biologically Informed Classifiers of Cancer Treatment Responses

A major difficulty limiting the translational potential of machine learning methods is low biological interpretability. Our lab develops biologically motivated classifiers of cancer outcomes by incorporating biological knowledge, networks, and databases with cancer omics.

Auslander Lab in the News

Selected Publications

  • A Deep Learning Approach Reveals Unexplored Landscape of Viral Expression in Cancer.

    Elbasir, A., Ye, Y., Schäffer, D.E., Hao, X., Wickramasinghe, J., Tsingas, K., Lieberman, P.M., Long, Q., Morris, Q., Zhang, R., et al. “A Deep Learning Approach Reveals Unexplored Landscape of Viral Expression in Cancer.” Nat Commun. 2023 Feb 11;14(1):785. doi: 10.1038/s41467-023-36336-z.

  • Mutated Processes Predict Immune Checkpoint Inhibitor Therapy Benefit in Metastatic Melanoma.

    Patterson A., Auslander N. “Mutated Processes Predict Immune Checkpoint Inhibitor Therapy Benefit in Metastatic Melanoma.” Nat Commun. 2022 Sep 19;13(1):5151. doi: 10.1038/s41467-022-32838-4.

  • In silico learning of tumor evolution through mutational time series.

    Auslander, N., Wolf, Y.I., Koonin, E.V. “In silico learning of tumor evolution through mutational time series.” Proc Natl Acad Sci U S A. 2019 May 7;116(19):9501-9510. doi: 10.1073/pnas.1901695116.

  • Seeker: alignment-free identification of bacteriophage genomes by deep learning.

    Auslander, N., Gussow, A.B., Benler, S., Wolf, Y.I., Koonin, E.V. “Seeker: alignment-free identification of bacteriophage genomes by deep learning.” Nucleic Acids Res. 2020 Dec 2;48(21):e121. doi: 10.1093/nar/gkaa856.

  • Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma.

    Auslander, N., Zhang, G., Lee, J.S., Frederick, D.T., Miao, B., Moll, T., Tian, T., Wei, Z., Madan, S., Sullivan, R.J., et al. “Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma.” Nat Med. 2018 Oct;24(10):1545-1549. doi: 10.1038/s41591-018-0157-9. Epub 2018 Aug 20.

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Dario C. Altieri, M.D.

  • President and Chief Executive Officer

  • Director, Ellen and Ronald Caplan Cancer Center

  • Robert and Penny Fox Distinguished Professor, Genome Regulation and Cell Signaling Program

Altieri is interested in how mechanisms of cellular adaptation or “plasticity” are universally exploited in cancer for disease maintenance and progression. Multiple cellular pathways of response to stress, metabolic rewiring, and control of cell death are invariably subverted in human tumors, and often confer more aggressive disease traits including the ability to disseminate to distant organs, or metastasis. A detailed, molecular, cellular, and genetic understanding of tumor plasticity could uncover new therapeutic targets and identify novel approaches to interfere with metastatic competence, which remains the primary cause of death for cancer patients.

Born in Milan, Italy, and educated at the University of Milan School of Medicine, Altieri is a physician-scientist trained in internal medicine and holds a postgraduate degree in clinical and experimental hematology. In 1987, he joined the Scripps Clinic and Research Foundation in La Jolla, California, first as a research fellow and later as a member of the faculty.

In 1994, Altieri became an associate professor at the Boyer Center for Molecular Medicine at Yale University School of Medicine, where he was named professor with tenure in 1999 and member of the Yale Cancer Center executive committee. In 2002, Altieri was recruited as the founding chair of the Department of Cancer Biology at the University of Massachusetts Medical School and Director of the UMass Memorial Cancer Center. Altieri joined the Institute as the Wistar Cancer Center Director and its first Chief Scientific Officer in September 2010. He was appointed as President and Chief Executive Officer of Wistar in 2015 while continuing to serve as Director of the recently renamed National Cancer Institute (NCI)-designated Ellen and Ronald Caplan Cancer Center.

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The Altieri Laboratory

215-898-3774

mcolelli@wistar.org

The Altieri Laboratory

The Altieri laboratory currently studies the role of mitochondria in cancer. The lab pursues the overarching hypothesis that multiple mitochondrial functions in bioenergetics, buffering of reactive oxidative species (ROS), inter-organelle communication with the endoplasmic reticulum (ER), and retrograde gene expression are invariably reprogrammed in malignancy and exploited to enable extraordinary plasticity and tumor heterogeneity for disease progression. Mechanistically, Altieri and his team have implicated these pathways in supporting tumor cell proliferation, evasion from multiple forms of cell death and, importantly, heightened tumor cell motility and invasion, leading to metastatic disease. To understand the role of tumor plasticity and mitochondrial reprogramming in disease progression and dissemination, Altieri uses a multidisciplinary collection of biochemical, cellular, and molecular approaches in vitro, xenograft, and genetic animal models of localized and metastatic disease, in vivo, and analysis of clinically-annotated primary patient samples. Although mechanistic in nature, Altieri lab research goals have clear translational and disease-relevant implications. Altieri’s work has demonstrated that therapeutic targeting of mitochondrial reprogramming in cancer is feasible, and may uniquely disable multiple mechanisms of disease progression, including metastatic competence across a broad spectrum of genetically heterogeneous tumors. Accordingly, a first-in-class, mitochondria-targeted small molecule inhibitor of the molecular chaperone Heat Shock Protein-90 (Hsp90) was developed and characterized by the Altieri laboratory (Gamitrinib) and has recently entered first-in-human clinical trial in patients with advanced cancer (ClinicalTrials.gov NCT04827810).

Staff
  • Research Assistant Professors

    Jagadish Ghosh, Ph.D.
    Michela Perego, Ph.D.

  • Associate Staff Scientist

    Irene Bertolini, Ph.D.

  • Postdoctoral Fellows

    Woomyee Bae, Ph.D.
    Minjeong Yeon, Ph.D.

  • Predoctoral Trainee

    Andrew Milcarek

Research

Multifunctional Survivin Signaling in Cancer

The Altieri laboratory is credited with the discovery and characterization of the survivin gene. Approaching 9,500 citations currently in PubMed, survivin is recognized as a fundamental cancer gene, a pleiotropic molecular hub for multiple pathways of cell survival, mitosis, adaptation to stress and metabolic reprogramming, as well as a validated therapeutic target in the clinic. Altieri’s contributions in this field have run the gamut from the discovery of survivin to the characterization of its unique role at the interface between cell death and mitosis in cancer, to clinical validation as a therapeutic target and predictive/prognostic disease biomarker.

Mitochondrial Proteostasis in Tumor Adaptation

Over the past decade, the Altieri lab’s work uncovered a novel role of protein folding quality control in mitochondria as a key driver of tumor progression. These studies elucidated mechanisms of protein homeostasis, or proteostasis maintained by Heat Shock Protein-90 (Hsp90) chaperones as well as AAA+ proteases in mitochondria, characterized their role in adaptive regulation of apoptosis, metabolic reprogramming and retrograde gene expression, and identified novel mechanisms of tumor adaptation to microenvironment stress stimuli, including hypoxia or exposure to molecular therapy.

Mitochondria and Metastasis

How tumors that switch to an inefficient glycolytic metabolism, i.e. the Warburg effect, manage to accomplish highly energy-demanding tasks of cell motility and invasion has long remained elusive. Altieri’s work demonstrated that mitochondrial oxidative phosphorylation is required to fuel membrane dynamics of cell motility, resulting in increased tumor chemotaxis, invasion and metastasis. Mechanistically, Altieri showed that this pathway involves the redistribution of energetically active mitochondria to the peripheral cytoskeleton of tumor cells, where they provide a concentrated, spatiotemporal energy source to power membrane lamellipodia dynamics, turnover of focal adhesion complexes, and sustained phosphorylation of cell motility kinases.

Mitochondrial Control of Tumor Plasticity

Recent findings from the Altieri group have demonstrated that mitochondrial reprogramming is a universal cancer trait that imparts unique plasticity to a full spectrum of tumor responses, from early-stage malignant transformation to full blown tumor growth, to regulation of go-or-grow decisions, the dynamic and reversible switch between cell proliferation and cell migration states. The Altieri lab showed that mitochondrial control of tumor plasticity involves panoply of signaling pathways, including generation of ROS, exosome-dependent intercellular communication, and stabilization of HIF1 resulting in a transcriptionally-active, pseudo-hypoxic state.

Novel Cancer Drug Discovery Approaches

The Altieri laboratory has pioneered the concept of targeting mitochondrial reprogramming for novel cancer therapeutics. The group uses a combination of mitochondrial-targeted peptidomimetic antagonists and small molecule ATPase inhibitors to disrupt mitochondrial Hsp90-directed protein folding, inhibit oxidative bioenergetics and abolish MFF cytoprotection at the mitochondrial outer membrane. In preclinical studies, these first-in-class mitochondrial-targeted agents (Shepherdin, Gamitrinib, MFF 8-11) were well-tolerated, demonstrated a unique “mitochondriotoxic” mechanism of action, and delivered potent, cytotoxic anticancer activity alone or in combination with molecular therapies in localized and disseminated tumor models, in vivo.

Altieri Lab in the News

  • Abs 2019-nCoV RNA virus - 3d rendered image on black background.

    TARGET: COVID-19

    News Outlet

    The emergence of Covid-19 has many scientists and life sciences industry CEOs shifting their priorities to battle the new coronavirus strain. Wistar’s researchers are in that mix, working with Plymouth Meeting’s Inovio on a DNA-based vaccine can

  • Cheyney U. Partners with The Wistar Institute for Life Science Program

    News Outlet

    Cheyney University and The Wistar Institute in Philadelphia have formed a partnership to expand life science research education, training and business development opportunities in Pennsylvania.

Selected Publications

  • Ghost Mitochondria Drive Metastasis Through Adaptive GCN2/AKt Therapeutic Vulnerability.

    Ghosh, J.C., Perego, M., Agarwal, E., Bertolini, I., Wang, Y., Goldman, A.R., Tang, H.Y., Kossenkov, A.V., Landis, C.J., Languino, L.R., et al. “Ghost Mitochondria Drive Metastasis Through Adaptive GCN2/AKt Therapeutic Vulnerability.” Proc Natl Acad Sci U S A. 2022 Feb 22;119(8):e2115624119. doi: 10.1073/pnas.2115624119.

  • A Cancer Ubiquitome Landscape Identifies Metabolic Reprogramming as Target of Parkin Tumor Suppression.

    Agarwal, E., Goldman, A.R., Tang, HY., Kossenkov, A.V., Ghosh, J.C., Languino, L.R.,  Vaira, V., Speicher, D.W., Altieri, D.C. “A Cancer Ubiquitome Landscape Identifies Metabolic Reprogramming as Target of Parkin Tumor Suppression.” Sci Adv. 2021 Aug 25;7(35):eabg7287. doi: 10.1126/sciadv.abg7287. Print 2021 Aug.

  • The Mitophagy Effector FUNDC1 Controls Mitochondrial Reprogramming and Cellular Plasticity In Cancer Cells.

    Li, J., Agarwal, E., Bertolini, I., Seo, J.H., Caino, M.C., Ghosh, J.C., Kossenkov, A.V., Liu, Q., Tang, HY., Goldman, A.R., Languino, L.R., Speicher, D.W., et al. “The Mitophagy Effector FUNDC1 Controls Mitochondrial Reprogramming and Cellular Plasticity In Cancer Cells.” Sci Signal. 2020 Jul 28;13(642):eaaz8240. doi: 10.1126/scisignal.aaz8240.

  • Small Extracellular Vesicle Regulation of Mitochondrial Dynamics Reprograms a Hypoxic Tumor Microenvironment.

    Bertolini, I., Ghosh, J.C., Kossenkov, A.V., Mulugu, S., Krishn, S.R., Vaira, V., Qin, J., Plow, E.F., Languino, L.R., Altieri, D.C. “Small Extracellular Vesicle Regulation of Mitochondrial Dynamics Reprograms a Hypoxic Tumor Microenvironment.” Dev Cell. 2020 Oct 26;55(2):163-177.e6. doi: 10.1016/j.devcel.2020.07.014. Epub 2020 Aug 10.

  • Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer.

    Caino, M.C., Seo, J.H., Wang, Y., Rivadeneira, D.B., Gabrilovich, D.I., Kim, E.T., Weeraratna, A.T., Languino, L.R., Altieri, D.C. ”Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer.” J Clin Invest. 2017 Oct 2;127(10):3755-3769. doi: 10.1172/JCI93172. Epub 2017 Sep 11.

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Wistar Scientists Honored, Speak at AIDS Education Month Event

Pride Month in Philadelphia, PA, is celebrated alongside another worthy cause: AIDS Education Month, an event series organized by the nonprofit Philadelphia FIGHT to raise awareness of those living with AIDS, AIDS treatments & healthcare and AIDS research. The Wistar Institute has collaborated with Philadelphia FIGHT for decades to advance their mission to cure HIV/AIDS.

At the opening celebration for AIDS Education Month on Thursday, June 1st, Philly FIGHT honored two Wistar senior scientists for their decades of contribution to HIV/AIDS research. Drs. Livio Azzoni and Emmanouil Papasavvas — each a senior scientist in the HIV program and Wistar Montaner Lab — received the Kiyoshi Kuromiya award, which honors a community Philadelphia activist, Kiyoshi Kuromiya that galvanized national and global awareness to the needs of persons living with HIV. Kuromiya organized with the Gay Liberation Front for gay rights and founded the Philly chapter of ACT UP to advocate for those impacted by the AIDS epidemic, and the award bearing his name recognizes those who have similarly impacted our community and made a difference to the lives of persons living with HIV.

Dr. Papasavvas was moved by the honor, and he took the opportunity to thank everyone involved in the collaborative work of the research process: “Research is not working alone; we all work together, trying to find the path to discover cures for all diseases, and right now, for HIV.”

Upon accepting his award, Dr. Azzoni also emphasized the teamwork necessary for science by speaking to the importance of both institutional support and patient focus in the search for an AIDS cure: “By doing patient-oriented research, we aim at involving all stakeholders in all stages, from design to implementation.” Both men received standing ovations from the crowd.

Dr. Montaner then joined the stage to participate in a panel discussion titled “The Evolution of HIV Research,” where he was accompanied by moderator and Director of the Philadelphia Department of Public Health’s Division of HIV Health, Dr. Kathleen A. Brady; Chief Scientific Officer and Medical Director of the Jonathan Lax Treatment Center, Dr. Karam Mounzer; Philadelphia FIGHT Director of Research, Emily Hiserodt, MPH; and longtime AIDS advocate, survivor and Chair of the BEAT-HIV Community Advisory Board, William Carter.

The panel sought to answer a compelling question: in the context of medical advances, why is research that seeks an HIV cure still important?

Panelists’ answers addressed several areas. William Carter, as an AIDS survivor, pointed out that an absolute cure would eliminate his need to take medication on an indefinite basis or receive regular bloodwork. Dr. Mounzer spoke to the fact that functional remission, while a tremendous achievement, still comes with reduced life expectancy and general stressors — like comorbidities and side-effects from the maintenance medications — relative to the HIV-negative population.

Dr. Montaner agreed with his fellow panelists on these points and expressed his belief in the macroscopic utility of reaching an HIV cure:

“First, investments made in understanding how HIV persists in somebody over a lifetime have benefited Society as a whole. We have one clear example: COVID. The clinical trials network and trained staff that supported COVID vaccine trials was made possible by the infrastructure that was already in place supporting studies on developing an HIV vaccine or novel therapies.

Second, reaching an HIV cure will hopefully remove the stigma directed towards persons living with HIV.”

Finally, scientific advances in one area of human health, Dr. Montaner emphasized, do not simply remain there: they carry over to different areas of study and move those fields forward, too. “If we can crack chronic infection in those living with HIV — or even just get closer towards that cure — we’re going to get insights into how to advance research into added diseases at the same time.”