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. An exciting emergent area of study is our uncovering of a major role for the nervous system in regulating cancer metastasis. 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.
RESEARCH
Unlocking the Mysteries of Metastasis & Gene Regulation
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METASTASIS BIOLOGY
PI & LAB PHILOSOPHY
Sohail Tavazoie MD PhD
Leon Hess Professor, Meyer Laboratory of Systems Cancer Biology
Director, Black Family Metastasis Center
Dr. Sohail Tavazoie is the Leon Hess Professor and Head of the Meyer Laboratory of Systems Cancer Biology at The Rockefeller University. He is the director of the Black Center for Metastasis Research at Rockefeller University and an attending medical oncologist at Memorial Sloan Kettering Cancer. He received his undergraduate degree from the University of California at Berkeley and his M.D. and Ph.D. degrees from Harvard Medical School. Following internship and residency training at Brigham and Women’s Hospital and postdoctoral training at Harvard, he conducted oncology fellowship training at Memorial Sloan Kettering Cancer Center. Sohail has been the recipient of the NIH Innovator Award, the Pershing Square Sohn Cancer Prize, the NCI Outstanding Investigator Award and the DOD Era of Hope Award. He is an elected member of the National Academy of Medicine and the past president of the American Society of Clinical Investigation.
Sohail's lab studies the molecular mechanisms underlying cancer metastasis and they apply these insights towards the development of novel experimental therapeutics that target the biology of metastatic disease. We believe 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.
King Faisal Yambire PhD
Postdoctoral Associate
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
Postdoctoral Associate
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
Postdoctoral Associate
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
Postdoctoral Associate
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
Postdoctoral Fellow
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.
Neil Neumann MD PhD
Postdoctoral Associate
Neil grew up in Des Moines, Iowa, and spent summers and winter breaks in Steamboat Springs, Colorado. He received his B.A. in Biophysics from Johns Hopkins University where he studied regulation of the L-arabinose operon under Dr. Robert Schleif. He attended Johns Hopkins School of Medicine in the physician-scientist training program where he received his medical degree. In the laboratory of Dr. Andrew Ewald, Neil conducted his graduate studies where he utilized three-dimensional organoid, timelapse imaging, and computational mechanical modeling to understand organogenesis of breast ductal epithelium and how that can eventually inform our understanding of breast cancer metastasis. In his spare time, Neil enjoys spending time with his wife and toddler, traveling, backcountry camping and hiking, as well as making special cooked meals and baked goods.
Jess Posada MD
Postdoctoral Associate
Jess is originally from San Francisco, CA and received her BS and MS in Cell and Molecular Biology. While in medical school at the University of Colorado, she participated in the Rockefeller University’s Year-Off Training Program for Medical Students in the laboratory of Dr. Tavazoie studying cancer metastasis. Jess helped establish a new therapeutic target in melanoma and found that administration of liver-X nuclear hormone receptor beta (LXRb) agonists led to the transcriptional activation of Apolipoprotein E (ApoE), thereby suppressing melanoma metastasis. After her medical degree, she completed the Anatomical Pathology residency program at Brigham and Women’s Hospital/Harvard Medical School. Jess rejoined the Tavazoie lab in 2023 to study mechanisms by which ApoE regulates cancer progression.
Alon Millet
Graduate Student
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 Mei
Graduate Student
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.
Ethan Seltzer
Graduate Student
Ethan is originally from New Jersey and received his B.S. in biological sciences from Cornell University with a minor in business. As an undergraduate, he studied membrane fusion in the ciliated protozoan Tetrahymena. He then relocated to New York City where he performed post baccalaureate research at The Hospital for Special Surgery studying the role of photosensitivity in autoimmune disorders such as lupus. In 2023, he joined the Tavazoie lab as a graduate student where he seeks to better understand the role of innervation in cancer metastasis. Ethan is an avid marathon runner, traveler, and lover of dogs.
Francesca Di Cristofano
Graduate Student
Originally from Pelham, New York, Francesca grew up in and out of her father’s lab, where she first became passionate about cancer biology. She later attended Brown University and graduated with an Sc.B. in Neurobiology in 2023. Now a Ph.D. student in the Tavazoie lab, Francesca is interested in intersecting these two fields as she seeks to understand how tumor-nerve interactions promote cancer metastasis. When she’s not in the lab, Francesca loves to cook, collage, watch movies, travel, and explore the city.
Nitay Ad-El
Graduate Student
Nitay grew up around Jerusalem, Israel, and later moved to the Tel-Aviv area. He was a paramedic for a few years until deciding to focus on science, doing a BSc in Biology in Tel-Aviv University. He later worked in the lab of Prof. Dan Peer, researching mRNA delivery systems. He joined the Tavazoie lab in 2024 to study interactions between metastatic cancers and the Central Nervous System.
Nandan Mandayan
Laboratory Manager
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 Wilson
Administrative Assistant
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 Perez
Animal Technician
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
Grants Administrator
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.
PUBLICATIONS
Neuronal substance P drives metastasis through an extracellular RNA–TLR7 axis.
Nature 2024
Tumour innervation is associated with worse patient outcomes in multiple cancers1,2, which suggests that it may regulate metastasis. Here we observed that highly metastatic mouse mammary tumours acquired more innervation than did less-metastatic tumours. This enhanced innervation was driven by expression of the axon-guidance molecule SLIT2 in tumour vasculature. Breast cancer cells induced spontaneous calcium activity in sensory neurons and elicited release of the neuropeptide substance P (SP). Using three-dimensional co-cultures and in vivo models, we found that neuronal SP promoted breast tumour growth, invasion and metastasis. Moreover, patient tumours with elevated SP exhibited enhanced lymph node metastatic spread. SP acted on tumoral tachykinin receptors (TACR1) to drive death of a small population of TACR1high cancer cells. Single-stranded RNAs (ssRNAs) released from dying cells acted on neighbouring tumoural Toll-like receptor 7 (TLR7) to non-canonically activate a prometastatic gene expression program. This SP- and ssRNA-induced Tlr7 gene expression signature was associated with reduced breast cancer survival outcomes. Therapeutic targeting of this neuro–cancer axis with the TACR1 antagonist aprepitant, an approved anti-nausea drug, suppressed breast cancer growth and metastasis in multiple models. Our findings reveal that tumour-induced hyperactivation of sensory neurons regulates multiple aspects of metastatic progression in breast cancer through a therapeutically targetable neuropeptide/extracellular ssRNA sensing axis.
Common human genetic variants of APOE impact murine COVID-19 mortality.
Nature 2022
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.
Nature, 2020
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.
PROJECTS
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.
METASTASIS THERAPY
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.
Norihiro Yamaguchi appointed Head of Lab at Laboratory of Cancer Biology and Genetics at the NIH/NCI
July, 2024
Dennis Hsu recruited to the University of Pittsburgh
September 2021
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!
Research Assistant
AVAILABLE POSITIONS
We seek a highly motivated, detail-oriented individual to join our efforts to study the basic principles of cancer metastasis, genomics and gene regulation in cancer. As a research assistant you will be trained in the analysis and interpretation of next-generation sequencing (NGS) data, originating from mouse experiments of cancer metastasis as well as patients, under the guidance of postdoctoral scientists and bioinformaticians. The successful applicant will be part of a fast-paced and dynamic team. The Tavazoie Lab will provide significant on-the-job training. We seek a candidate who is motivated and can take independent initiative. This is an excellent opportunity for someone looking to gain experience to move into a PhD or MD-PhD program within a couple of years, based on the new skillset they develop at Rockefeller University (though, this is not a requirement). Exposure to NGS data analysis and working understanding of code and script preferred. Training in statistics or machine learning is a plus. Please use the Contact Us section below to send your CV and Cover Letter.
Xuhang Liu named Assistant Professor of at the Roswell Park Comprehensive Cancer Center
December, 2022
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Nneoma Adaku defends her thesis on a role for the ApoE2 genetic variant as a promoter of melanoma metastasis!
December, 2022
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Ryan Moy named Assistant Professor at Columbia University!
June, 2021
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
Aug 2021
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!!
