METASTASIS BIOLOGY & GENE REGULATION
Rockefeller Laboratory of Systems Cancer Biology
Metastasis, or the spread of cancer from a primary tumor to a distal organ, is the primary cause of cancer death. Despite this fact, the molecular mechanisms and fascinating biology underlying metastatic progression are poorly understood. Scientists in our lab are discovering the critical genes and cellular processes that drive this process and have provided the first evidence for a role of hereditary genetics in human metastasis formation. We are applying this understanding towards development of the next generation of cancer therapeutics that selectively target metastatic disease. By studying how cancer cells turn genes on and off during metastasis, our scientists have also uncovered new mechanisms of gene regulation mediated by transfer RNAs. We employ a broad range of approaches and technologies, including many we have developed to aid our studies. Our overarching goals are to understand metastasis biology as a means of developing curative anti-metastatic therapies and to train future leaders in biomedical research.
Unlocking the Mysteries of Metastasis & Gene Regulation
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PI & LAB PHILOSOPHY
Sohail Tavazoie MD PhD
Leon Hess Professor, Meyer Laboratory of Systems Cancer Biology
Director, Black Family Metastasis Center
Sohail graduated from the University of California at Berkeley, completed an MD-PhD program at Harvard-MIT followed by Internal Medicine residency training at Brigham & Women's Hospital/Harvard and medical oncology fellowship training at Memorial Sloan Kettering Cancer Center. In 2009, he was recruited to Rockefeller University as Head of the Laboratory of Systems Cancer Biology and was promoted to Professor in 2018. Sohail is the president of the American Society of Clinical Investigation and a member of the National Academy of Medicine's Emerging Leaders forum. Sohail believes that the best science happens when diverse people come together in a supportive, collaborative and fun environment. Our lab members tend to be friendly, creative and bold. Our lab is very diverse--scientifically, internationally, racially and with respect to sexual orientation. Scientists are given the space to grow but also provided extensive mentorship--honing speaking, writing, teaching, grant-writing, networking, chalk-talk and social skills that are critical for success at top academic institutions. We strive to do science that is rigorous, impactful and creative. More than 90% of students, postdocs and bachelors students have succeeded in obtaining their desired positions in leading academic and biotech/industry position. Recent postdocs and students are faculty members leading their own labs at top institutions including UCSF, Yale, Columbia, Charite/Berlin, Bergen and UPenn.
Mira Patel MD
Mira hails from Rochester, NY and received her B.A. in Biological Sciences and Government from Cornell University. She attended medical school at Johns Hopkins University, where she spent dedicated time in the lab studying the glioblastoma immune microenvironment. She subsequently completed her clinical residency in Radiation Oncology at Memorial Sloan Kettering Cancer Center. She joined the Tavazoie Lab in 2020 as a Rockefeller Clinical Scholar to study genetic modifiers of cancer metastasis. In her spare time, she enjoys running, the outdoors, and exploring the NYC restaurant scene.
King Faisal Yambire PhD
King grew up in Ghana and obtained his undergraduate degree from the University of Ghana. He completed his PhD in Neuroscience at the University of Goettingen in German, studying signaling between the lysosome and mitochondria. King joined the Tavazoie lab in 2020 and is excited to study the roles of mitochondrial tRNAs in physiology and cancer metastasis. He is a super fan of Real Madrid and Arsenal. He engages in most sporting activities, especially soccer and volleyball. He also likes to travel and try new things when not at the bench.
Veena Padmanaban PhD
Veena is originally from India and received her undergraduate training from SRM University in Chennai, India. She then conducted graduate training in the lab of Andrew Ewald at Johns Hopkins where she used imaging methods to elucidate the mechanisms underlying breast cancer adhesion, invasion and progression.
Alexandra Pinzaru PhD
Alexandra was born and raised in Romania, where she developed a passion for studying biology. She moved to Germany for her undergraduate studies and received her BSc in Biochemistry and Cell Biology from Jacobs University Bremen. Alexandra migrated further west to the US, for her PhD. During her graduate studies, she investigated the impact of telomere dysfunction on cancer development in the lab of Dr. Agnel Sfeir at NYU Langone Health. In November 2018, Alexandra joined the Tavazoie lab as a postdoc associate, in order to decipher the regulation of tRNA isoacceptors in cancer metastasis. Outside of lab, Alexandra enjoys visiting museums, browsing bookstores, cooking and dancing.
Mai Takahashi MD MPH
Mai was born and grew up in Chiba, Japan where she attended medical school. She moved to the US and obtained MPH at Harvard School of Public Health, and completed internal medicine training at Mount Sinai Beth Israel. She has previous clinical research experiences in the area of head and neck cancer. She joined the Tavazoie lab in 2022 to study cancer metastasis mechanisms and explore potential cancer therapeutic targets.
Qiushuang Wu PhD
Q grew up in China, she received her undergrad degree from Wuhan University. She did her PhD training with Dr. Ariel Bazzini at Stowers Institute for Medical Research. During her PhD, she studied the function of ribosome to regulate gene expression, at both mRNA decay and translation regulation. In Aug 2022, she joined Tavazoie lab, trying to apply her knowledge at post-transcriptional regulation into cancer biology.
Alon was born in Israel but grew up in New Jersey, and he completed his joint B.S./M.S. in Molecular, Cellular, and Developmental Biology from Yale University in 2020. He joined the Tavazoie Lab in 2021 with the Tri-Institutional Program in Computational Biology and Medicine and aims to leverage both wet and dry lab approaches to study central questions in tumor systems immunology. If he's not in the lab, Alon can be found either cooking and baking in the kitchen or playing piano in the most hermetically soundproofed room he can find.
Wenbin grew up in Guangzhou and completed his undergraduate training in Biology and Mathematics at Peking University. For his PhD, he is applying computational and functional approaches to study the regulation of metastasis. In his spare time, he enjoys joining his girlfriend in New Haven.
Nandan has conducted past research in the areas of oncogenesis and stem cell biology. He is lab manager and assists lab members in molecular and animal studies.
Michelle is an English major with a background in cultural studies, born in Costa Rica and raised in Texas. She specializes in organizational skills with the purpose to simplify the lives of others. Michelle loves warm weather, swimming in the ocean and watching movies with her family along with travel, yoga and holistic wellness.
Bryan was born in Peru and grew up in New York City. He attended Borough Manhattan Community College and Hunter College and holds a Bachelor’s degree in Psychology. During Bryan’s undergraduate studies, he joined the lab of Dr. Thomas Preuss and studied neuroethological questions in African Cichlid fish. He joined the Tavazoie Lab as an Animal Technician where he works on maintaining the mouse colony, genotyping, and helping lab members with their daily tasks. He also contributes to a project focused on genetic mouse models of Apo-E and lipoprotein metabolism. During his free time, Bryan likes to explore NYC and beyond, listen to all kinds of music, play sports, and spend time with his dog Maximus and his birds (Cockatiels).
Emilie Wang PhD MBA
Emilie is a Canadian-New Yorker who completed a PhD program at the Albert Einstein College of Medicine and received an MBA from the NYU Stern School of Business. Before joining the Tavazoie Lab, she worked for a tech startup focused on transforming care for cancer patients and abroad for Médecins sans Frontières.
Common human genetic variants of APOE impact murine COVID-19 mortality.
Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world's population1 and associated with Alzheimer's disease, atherosclerosis and anti-tumour immunity2-5, affect COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the APOE2 or APOE4 variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent APOE3 allele. APOE2 and APOE4 mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, our results also show that APOE genotype is associated with survival in patients infected with SARS-CoV-2 in the UK Biobank (candidate variant analysis, P = 2.6 × 10-7). Our findings suggest APOE genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess APOE genotyping as a means of identifying patients at high risk for adverse outcomes.
Tumoural activation of TLR3-SLIT2 in endothelium drives metastasis.
Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.
LXR/APOE ACTIVATION RESTRICTS INNATE IMMUNE SUPPRESSION IN CANCER. CELL 2018
Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer1. Here we use mouse models of breast and lung cancer to investigate whether endothelial cells also have active 'instructive' roles in the dissemination of cancer. We purified genetically tagged endothelial ribosomes and their associated transcripts from highly and poorly metastatic tumours. Deep sequencing revealed that metastatic tumours induced expression of the axon-guidance gene Slit2 in endothelium, establishing differential expression between the endothelial (high Slit2 expression) and tumoural (low Slit2 expression) compartments. Endothelial-derived SLIT2 protein and its receptor ROBO1 promoted the migration of cancer cells towards endothelial cells and intravasation. Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer. Conversely, deletion of tumoural Slit2 enhanced metastatic progression. We identified double-stranded RNA derived from tumour cells as an upstream signal that induces expression of endothelial SLIT2 by acting on the RNA-sensing receptor TLR3. Accordingly, a set of endogenous retroviral element RNAs were upregulated in metastatic cells and detected extracellularly. Thus, cancer cells co-opt innate RNA sensing to induce a chemotactic signalling pathway in endothelium that drives intravasation and metastasis. These findings reveal that endothelial cells have a direct instructive role in driving metastatic dissemination, and demonstrate that a single gene (Slit2) can promote or suppress cancer progression depending on its cellular source.
METASTASIS BIOLOGY & GENETICS
We have identified critical genes that regulate metastasis formation in common cancers. We seek to understand the molecular and cellular mechanisms by which these genes regulate metastasis formation within the metastatic niche. We have also uncovered the first evidence for a hereditary genetic basis of human metastasis. We are employing powerful molecular, genetic, biochemical, pharmacological, imaging, and clinical association approaches to discover additional heritable genes underlying cancer metastasis and to understand their mechanisms of action.
Our discovery of critical genes that regulate metastasis formation has unveiled new therapeutic paths. We are developing small-molecule and antibody-based therapeutics as a means of preventing and eradicating metastatic disease. We have advanced these approaches into human clinical testing with our collaborators at the biotechnology company Inspirna, where proof-of-concept for two of these therapies has been observed in advanced stage and refractory cancers. We are working towards developing anti-metastatic combination regimens that will be curative.
TRNA-MEDIATED GENE REGULATION IN CANCER
We have found that as cancers become metastatic, specific tRNAs become modulated. This is surprising, since tRNAs are thought to be static adaptor molecules. Such tRNA modulations enable enhanced translation of pro-metastatic genes. We are employing molecular, genetic, and biochemical approaches to understand the basic mechanisms by which this non-canonical gene regulatory mechanism operates.
GENE REGULATION BY TRNA-DERIVED FRAGMENTS IN HEALTH AND IN CANCER
tRNAs have been observed to undergo cleavage across species upon exposure of cells to stress. We have observed that specific tRNAs become fragmented--generating small trans-acting tRNA fragments that regulate gene expression via interactions with RNA binding proteins. We are studying the mechanisms of generation and action of such stress-induced tRFs in nematode, mouse, and human cells. By understanding this process, we aim to exploit tRNA-fragmentation as an anti-cancer therapy.
Xuhang Liu named Assistant Professor of at the Roswell Park Comprehensive Cancer Center
Nneoma Adaku defends her thesis on a role for the ApoE2 genetic variant as a promoter of melanoma metastasis!
Mira Patel awarded a prestigious Damon Runyon Physician scientist Fellowship award!
Ryan Moy named Assistant Professor at Columbia University!
We are incredibly excited for Ryan Moy who will be starting as a faculty member at Columbia University as an Assistant Professor. Ryan, who has already secured NIH K funding will be a physician scientist focusing on gastrointestinal cancer progression. Congrats Ryan!! We look forward to your continued success!!
Ben Ostendorf named Group leader and faculty member at world-renowned Charite University in Berlin
We are so thrilled that our amazing Ben Ostendorf has been selected to be Group Leader and faculty member at the Charite University in Berlin--a top biomedical research center in Germany that has hosted more than half of all German Physiology or Medicine Nobel Prize winners. Given your remarkable abilities, we're sure you'll keep up the tradition Ben!!
Ben Ostendorf named Group leader and faculty member at world-renowned Charite University in Berlin
We are so thrilled that our amazing Ben Ostendorf has been selected to be Group Leader and faculty member at the Charite University in Berlin--a top biomedical research center in Germany that has hosted more than half of all German Physiology or Medicine Nobel Prize winners. We're sure you'll keep up the tradition Ben!!
Veena receives highly prestigious Hope Funds Fellowship Award
We are so excited that Veena Padmanaban has been selected a Hope Funds for Cancer Research Fellow. This national prestigious award will fund Veena's highly innovative work focused on the molecular regulation of cancer metastasis. Veena, you make it all look so easy!
Dennis Hsu recruited to the University of Pittsburgh
We are very proud that Dennis Hsu, who was recently awarded a large Damon Runyon research award and will continue to pioneer computational and experimental approaches to the study of cancer progression at the University of Pittsburgh. Congrats, we will miss your broad brilliance in bioinformatics, metabolism, and medical oncology!
Jose Ledo attains faculty position at the Medical University of South Carolina!
A huge Congrats to Jose for obtaining a faculty position at the Medical University of South Carolina. Jose's lab will study the role of neuro-immune interactions in Alzheimer's disease. Keep up the great work Jose!
Computational Postdoctoral Scientist
We seek a highly talented Computational Scientist who is passionate about the biology and genetics of cancer metastasis to work within the Laboratory of Systems Cancer Biology and two associated laboratories funded by a prestigious National Cancer Institute Metastasis Network Award. Suitable applicants will be able to: provide effective data analysis; organize genome-wide transcriptomics and genomic DNA information; create new pipelines for genomic data, maintain existing pipelines and help to interpret results.
We are especially interested in postdoctoral scientists with expertise and training in diverse disciplines who may be new to cancer biology.