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. Our lab is identifying the key genes and cellular processes underlying this process and recently uncovered a hereditary genetic basis for human cancer progression and metastasis. 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 on and off genes during the metastatic process, we have also discovered non-canonical modes 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.
Unlocking the Mysteries of Metastasis & Gene Regulation
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Sohail Tavazoie MD PhD
Leon Hess Professor & HHMI Faculty Scholar
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 has received the Rita Allen Scholar and DOD Era of Hope awards as well as the Pershing Square Sohn Prize. He is a member of the editorial board of Cell, an elected member of the American Society of Clinical Investigation, and a member of the National Academy of Medicine's Emerging Leaders forum.
Eiko was born and raised in Yokohama, Japan. She obtained a bachelor’s degree in Chemistry from University of Washington and received her M.S. in Molecular Biology from University of California, Santa Barbara. After ~10 yrs of bench work, she joined the Tavazoie lab as a lab administrator in 2015. She loves to explore the intricacy of human body movements and shares her own experience and practice in her yoga class.
BERNARDO TAVORA PHD
Bernardo received his MSc degree from the University of Lisbon, Portugal and his Ph.D. from the University of London, UK. Joined Tavazoie lab as a postdoc and currently is the Hope Funds for Cancer Research Lucylee Chiles Research Fellow.
XUHANG LIU PHD
Xuhang is from Guangzhou (China), a city best known for its Cantonese cuisine and culture. After obtaining his B.S. in Biology from Peking University, Beijing, he did his Ph.D. thesis on elucidating mammalian microRNA biogenesis pathways at the University of Pennsylvania. He joined the Tavazoie laboratory in 2013 to study the roles that microRNAs and other non-coding RNAs play in cancer metastasis.
BENJAMIN OSTENDORF MD
Benjamin received his medical degree from the University of Freiburg in Germany before becoming a resident in Internal Medicine at the Charité in Berlin. In 2015 he joined the Tavazoie lab to study the mechanisms of breast cancer metastasis and potential therapies. While not at the bench he enjoys playing the guitar and cycling New York.
Maria grew up on Long Island, and completed her undergraduate training in Molecular Biophysics and Biochemistry at Yale University in 2015. Maria joined the Tavazoie laboratory in 2017 as part of the Tri-I MD-PhD program, to study the role of tRNAs in cancer metastasis. In her spare time, Maria enjoys singing, baking, and skiing.
NORI YAMAGUCHI MD
Norihiro was born, raised, and educated in Osaka, Japan. It was the first time for him to go outside of 3 miles radius from his home in Osaka when he did clinical oncology externship at Massachusetts General Hospital as a final year medical student. Life is so unpredictable to see himself doing research in NY. Making a bridge from science to medicine is his task.
RYAN MOY MD PHD
Ryan grew up in Southern California and received a B.S. in Molecular Biophysics and Biochemistry from Yale University. He then pursued an MD-PhD at the University of Pennsylvania, where he worked in the lab of Dr. Sara Cherry to identify novel innate immune pathways that control insect-borne viral infections. He completed an internal medicine residency at New York-Presbyterian Hospital-Cornell and is currently a medical oncology fellow at Memorial Sloan Kettering Cancer Center. Ryan joined the Tavazoie lab in 2018 to elucidate mechanisms that drive colorectal and gastric cancer metastasis. In his spare time, Ryan enjoys travel, exercise and running marathons.
DENNIS HSU MD
Dennis is from the Bay Area and obtained his B.S. in Engineering Physics from the University of California, Berkeley. He traveled to the midwest for medical school at the Cleveland Clinic, completed his medicine residency at the University of Michigan, and is currently a medical oncology fellow at Memorial Sloan Kettering Cancer Center. His prior research experiences have involved topics ranging from biomedical optics to studying KRAS biology in colon cancer. He joined the Tavazoie lab in 2017 to study tRNA modulations in cancer while completing his oncology fellowship. In his spare time, Dennis enjoys traveling, trying new foods, and keeping up with new technologies.
Veena Padmanaban PhD
I am originally from India and received my undergraduate training from SRM University in Chennai, India. I then conducted graduate training in the lab of Andrew Ewald at Johns Hopkins where I used imaging methods to elucidate the mechanisms underlying breast cancer adhesion, invasion and progression.
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.
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.
Nneoma spent her early childhood in Bronx, NY and received her B.S. in Molecular, Cellular, and Developmental Biology from Yale University in 2015, where she remained for a year to continue her studies on DNA repair inhibitors produced by Ecuadorian fungal endophytes. She was happy to finally return to New York City in 2016 as a member of the Tri-Institutional MD-PhD program and joined the Tavazoie Lab in 2018 with the aim of identifying new mechanisms and therapeutic targets for cancer metastasis. When not in lab she enjoys traveling, biking, soccer, bingeing TV shows, and going to concerts.
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.
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.
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.
LXR/APOE ACTIVATION RESTRICTS INNATE IMMUNE SUPPRESSION IN CANCER. CELL 2018
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.
MODULATED EXPRESSION OF SPECIFIC TRNAS DRIVES GENE EXPRESSION AND CANCER PROGRESSION. CELL 2016
Transfer RNAs (tRNAs) are primarily viewed as static contributors to gene expression. By developing a high-throughput tRNA profiling method, we find that specific tRNAs are upregulated in human breast cancer cells as they gain metastatic activity. Through loss-of-function, gain-of-function, and clinical-association studies, we implicate tRNAGluUUC and tRNAArgCCG as promoters of breast cancer metastasis. Upregulation of these tRNAs enhances stability and ribosome occupancy of transcripts enriched for their cognate codons. Specifically, tRNAGluUUC promotes metastatic progression by directly enhancing EXOSC2 expression and enhancing GRIPAP1-constituting an "inducible" pathway driven by a tRNA. The cellular proteomic shift toward a pro-metastatic state mirrors global tRNA shifts, allowing for cell-state and cell-type transgene expression optimization through codon content quantification. TRNA modulation represents a mechanism by which cells achieve altered expression of specific transcripts and proteins. TRNAs are thus dynamic regulators of gene expression and the tRNA codon landscape can causally and specifically impact disease progression.
Tumoural activation of TLR3-SLIT2 in endothelium drives metastasis. Nature, 2020
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.
Portfolio of Work
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 molecular, genetic, biochemical, pharmacological, imaging, and clinical association approaches to understand this biology.
Our discovery of critical genes that regulate metastasis formation has unveiled new therapeutic paths. We have developed small-molecule and antibody-based therapeutics as a means of preventing and eradicating metastatic disease. We have advanced these approaches into human clinical testing. We wish to develop curative anti-metastatic combination regimens.
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.
New postdoc (Mira) joins lab and is awarded Rockefeller Clinical Scholars Award!
We are thrilled to have Mira Patel join our lab. Mira obtained her medical degree from Johns Hopkins, where she conducted innovative studies on Glioblastoma immunotherapy. She then trained in Radiation Oncology at MSKCC. Mira will study the biology of metastatic progression. Welcome Mira!
New postdoc (King) joins the lab!
We are thrilled to have King Faisal Yambire join our lab. King is originally from Ghana and completed his graduate work in Germany, where he made fundamental discoveries pertaining to signaling between lysosomes and mitochondria. King will be investigating the role of mitochondrial tRNAs in physiology and cancer metastasis.
Congrats Nneoma on getting an amazing 4% on your 1st F30 submission!
Congrats to Nneoma for rocking her F30 submission and breaking our lab's record with her 4% score on her 1st submission!
January 25, 2020
We seek highly talented postdoctoral applicants who are passionate about the biology of cancer metastasis or non-canonical modes of gene regulation by tRNAs and tRNA fragments. We are especially interested in scientists with expertise and training from diverse disciplines who are new to cancer biology.