Heads of Laboratories
Sohail Tavazoie, M.D., Ph.D.
Senior Attending Physician
Leon Hess Associate Professor
Elizabeth and Vincent Meyer Laboratory of Systems Cancer Biology
Metastasis, the spread of cancer cells from a primary tumor to distal organs, accounts for the overwhelming majority of human deaths from solid cancers. Dr. Tavazoie’s laboratory employs a systems biological approach that integrates molecular, cellular, animal and clinical observations to identify and characterize key molecular regulators of this complex process, with the ultimate goal of developing novel therapies aimed at its prevention and treatment.
This year, over eight million people will die from cancer globally. For a large fraction of these individuals, the cause of death will be metastatic colonization of distant organs by cancer cells. While the impact of this process on human mortality has long been recognized, the molecular mechanisms that underlie cancer metastasis have only recently begun to be intensely studied. As is the case with developmental programs, metastatic progression by cancer cells requires the proper expression of effector genes that drive specific cellular and cell-biological phenotypes. Dr. Tavazoie is a cancer biologist and medical oncologist who is fundamentally interested in how such prometastatic gene expression programs are established in cancer cells, how they enable cancer cells to metastasize and how such programs emerge during cancer progression.
Dr. Tavazoie’s laboratory employs a combination of molecular, genomic, biochemical, genetic, imaging and computational approaches to study this process. These insights, combined with in vitro, in vivo, genetic and clinical association observations, are used to generate an integrated molecular and biological model of metastatic progression. This systematic approach has revealed that the acquisition of the metastatic phenotype by breast cancer cells requires the silencing of specific small noncoding RNAs (microRNAs). The silencing of these small RNAs leads to the enhanced expression of their target genes, which the lab identified to be promoters of metastatic phenotypes. Dr. Tavazoie’s lab has generalized their findings to other prevalent cancers arising from distinct developmental lineages such as melanoma and colorectal cancer and have found that in these cancers, modulated expression of tissue-specific sets of small RNAs achieve enhanced metastatic outcomes. By experimentally modulating these metastasis regulatory microRNAs, the metastatic activity of cancer cells can be strongly impacted. Importantly, the expression levels of these specific microRNAs and their target genes in human cancer specimens support their functionally implicated roles in cancer.
The use of these microRNAs as molecular probes has enabled Dr. Tavazoie to very efficiently uncover the cellular phenotypes they control and to implicate their downstream target genes and pathways as novel effectors of metastatic progression. His lab has established mouse metastasis systems that model the progression of prevalent human cancers, such as triple negative breast cancer, melanoma and colorectal cancer. These cancers were chosen because as a whole, they impact an exceedingly large number of patients globally; effective targeted therapies that prevent metastatic progression by these malignancies do not exist; and their derivation from three distinct developmental lineages makes it possible to determine how cells from diverse tissue origins achieve common phenotypic outcomes. To ensure the generality of their conclusions, Dr. Tavazoie’s lab uses xenograft, patient-derived xenograft, immunocompetent and genetically initiated models.
Dr. Tavazoie’s overarching goals are to systematically identify the gene networks that operate downstream of these small RNA regulators, to determine how the activities of these small RNAs are modulated during the acquisition of metastatic capacity, to uncover the cell-biological and cellular roles of these microRNA regulatory pathways in cancer, to determine the physiological or developmental roles of these regulators and their key target genes, and to identify and therapeutically target key vulnerabilities within these networks in cancer. The insights gained from these studies could reveal previously uncharacterized mechanisms of gene expression regulation that might operate in normal cells and could reveal new avenues for therapeutic intervention in patients at risk for metastatic relapse.
- Furlow P.W., Zhang S., Soong T.D., Halberg N., Goodarzi H., Mangrum C., Wu G.Y., Elemento O., and Tavazoie S.F.* Mechanosensitive pannexin-1 channels mediate metastatic cell survival in the microvasculature. Nature Cell Biology, 2015 Jul;17(7):943-52. doi: 10.1038/ncb3194.
- Goodarzi H., Liu X., Zhang S., Fish L., and Tavazoie S.F.* Endogenous tRNA-derived fragments suppress breast cancer progression via YBX1 displacement. Cell, 2015 May 7;161(4):790-802. Doi: 10.1016/j.cell.2015.02.053.
- Ross J.B., Huh D., Noble L.B., and Tavazoie S.F.* Molecular determinants of primary and metastatic tumor re-initiation in breast cancer. Nature Cell Biology, 2015 May;17(5):651-64. doi: 10.1038/ncb3148.
- Alarcon C., Lee H.L., Goodarzi H., and Tavazoie S.F.* N6-methyladenosine marks primary microRNAs for processing.. Nature, 2015 Mar 26;519(7544):482-5. doi: 10.1038/nature14281.
- Loo J., Scherl A., Nguyen A., Man F.Y., Zeng Z., Saltz L., Paty P.B., and Tavazoie S.F.* Extracellular metabolic energetics drive colorectal cancer progression. Cell, 2015 January 29; 160(3):393-406. doi:10.1016/j.cell.2014.12.018.
- Goodarzi H., Zhang S., Buss C.G., Fish L., Tavazoie S.* and Tavazoie S.F.* Metastasis-suppressor transcript destabilization through TARBP2 binding of mRNA hairpins, Nature, 2014 July9; doi:10.1038/nature13466.
- Pencheva N., Buss C. G., Posada J., Merghoub T., Tavazoie, S.F.* Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation. Cell, 2014 Feb 27;156(5):986-1001. Doi: 10.1016/j.cell.2014.01.038.
- Pencheva N., Tran H., Buss C., Huh D., Drobnjak M., Busam K., and Tavazoie S.F.* Convergent multi-miRNA Targeting of ApoE Drives LRP1/LRP8-Dependent Melanoma Metastasis and Angiogenesis. Cell, 2012 Nov 21;151(5):1068-82. doi: 10.1016/j.cell.2012.10.028.
- Png K.J., Halberg N, Yoshida M, and Tavazoie S.F.* A miRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature, 2011 Dec 14;481(7380):190-4. doi:10.1038/ nature10661.
Dr. Tavazoie received his undergraduate degree from the University of California, Berkeley, his Ph.D. from Harvard University and his M.D. from Harvard Medical School and the Harvard-MIT Division of Health Sciences and Technology. Following a residency and internship in internal medicine at Harvard’s Brigham and Women’s Hospital, he joined Memorial Sloan Kettering Cancer Center as a clinical fellow in 2005 and became a research fellow in medical oncology in 2006. He joined Rockefeller as an assistant professor in 2009 and was named associate professor in 2015.
In 2009 Dr. Tavazoie was the recipient of the NIH Director’s New Innovator Award and a combined American Society of Clinical Oncology and American Association for Cancer Research Young Investigator Award. He was also named a Rita Allen Foundation Scholar, a Sidney Kimmel Foundation for Cancer Research Scholar and a Sinsheimer Foundation Scholar, and he received an Emerald Foundation Young Investigator Award. He is also a Department of Defense Era of Hope Scholar. Dr. Tavazoie is an attending medical oncologist at Memorial Sloan Kettering Cancer Center.
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