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. 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 made basic discoveries, uncovering surprising and non-canonical modes of gene regulation mediated by transfer RNAs. We employ a broad combination 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, NIH new innovator, and the 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.
Shahnoza was born and raised in Dushanbe, Tajikistan. She went to college in Washington, DC where she received her Nursing and Biology degrees. During her undergraduate studies, she investigated the role of microRNAs in human cancer metastasis in Dr. Kumar’s lab. In Tavazoie lab, she is super excited to study the potential importance of tRNAs as biomarkers of metastasis in cancer and wants to be as cool as Dr. Sohail in the future.
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.
MARIA LIBERTI PHD
Maria was born and raised in northern New Jersey. After graduating from Lafayette College in 2013 and receiving a Bachelor of Science with honors in Biology, she went on to complete her Ph.D. in Biochemistry from Cornell University and studied therapeutic targeting of the Warburg Effect in cancer in Dr. Jason Locasale’s laboratory. Maria joined the Tavazoie laboratory in 2018 for her postdoctoral training as an NCI K00 fellow and is excited to study metabolic regulation in cancer metastasis. On her free time, she enjoys traveling and trying new cuisines.
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.
Christina obtained medical training at University of Goettingen, Germany and joined our lab 2019. She is studying the molecular mechanisms underlying colorectal cancer metastasis using molecular and biochemical methods in collaboration with Ryan Moy. In her spare time, she enjoys swing dancing, underwater rugby, and playing the acoustic guitar.
Jenny graduated from New York University in 2018 with a bachelor’s in Biology. She started research studying the role of microRNAs in stem cell reprogramming, and in college, helped develop lineage tracing tools in C. elegans. In her free time, she enjoys traveling, hot yoga, and trying new restaurants.
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.
N6-METHYLADENOSINE MARKS PRIMARY MICRORNAS FOR PROCESSING. NATURE 2015
The first step in the biogenesis of microRNAs is the processing of primary microRNAs (pri-miRNAs) by the microprocessor complex, composed of the RNA-binding protein DGCR8 and the type III RNase DROSHA. This initial event requires recognition of the junction between the stem and the flanking single-stranded RNA of the pri-miRNA hairpin by DGCR8 followed by recruitment of DROSHA, which cleaves the RNA duplex to yield the pre-miRNA product. While the mechanisms underlying pri-miRNA processing have been determined, the mechanism by which DGCR8 recognizes and binds pri-miRNAs, as opposed to other secondary structures present in transcripts, is not understood. Here we find in mammalian cells that methyltransferase-like 3 (METTL3) methylates pri-miRNAs, marking them for recognition and processing by DGCR8. Consistent with this, METTL3 depletion reduced the binding of DGCR8 to pri-miRNAs and resulted in the global reduction of mature miRNAs and concomitant accumulation of unprocessed pri-miRNAs. In vitro processing reactions confirmed the sufficiency of the N(6)-methyladenosine (m(6)A) mark in promoting pri-miRNA processing. Finally, gain-of-function experiments revealed that METTL3 is sufficient to enhance miRNA maturation in a global and non-cell-type-specific manner. Our findings reveal that the m(6)A mark acts as a key post-transcriptional modification that promotes the initiation of miRNA biogenesis.
Portfolio of Work
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. To this end, 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.
Ryan named Damon Runyon Fellow!
Congrats to Ryan Moy who just received a prestigious Damon Runyon Fellowship Award for his studies aimed at systematically elucidating the mechanisms underlying metastasis by gastrointestinal cancers.
New postdoc (Veena) joins lab and wins American Society of Cell Biology Award!
We are thrilled to have Veena Padmanaban join our lab. She comes to us from Johns Hopkins, where she made major discoveries underlying the cellular and cell biological mechanisms underlying cancer adhesion, invasion, and progression in Andy Ewald's lab, for which she just awarded the ASCB Merton Bernfield Memorial Award!
Congrats to Maria on her F31 Award!
Congrats to Maria on being awarded an F31 graduate student fellowship award on her proposed graduate work focused on understanding translational deregulation in breast cancer progression.
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.