"https://scholar.google.com/citations?hl=en&user=prWSX04AAAAJ." 2024.
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Research Projects
Quiescent (G0) cells are observed as a clinically relevant population in leukemias and other tumors associated with poor survival. G0 is a unique, nonproliferative phase that provides an advantageous escape from harsh situations like chemotherapy, allowing cells to evade permanent outcomes of senescence, differentiation, and apoptosis in such tumornegative environments. Instead, the cell is suspended reversibly in an assortment of transition phases that retain the ability to return to proliferation and contribute to tumor persistence. G0 demonstrates a switch to a distinct gene expression program, upregulating the expression of mRNAs and regulatory non-coding RNAs required for survival. Quiescence regulators that maintain the quiescent, chemoresistant state remain largely undiscovered.
Our studies revealed that specific posttranscriptional regulators, including AU-rich elements (AREs), microRNAs, RNA-protein complexes (RNPs), ribosome factors and RNA modifiers, are directed by G0- and chemotherapy- induced signaling to alter expression of clinically important genes. AU-rich elements (AREs) are conserved mRNA 3’-untranslated region (UTR) elements. MicroRNAs are small noncoding RNAs that target distinct 3’UTR sites. These associate with RNPs, ribosome associated factors and their modifiers to control post-transcriptional expression of cytokines and growth modulators. Their deregulation leads to a wide range of diseases, including tumor growth, immune and developmental disorders.
We identified post-transcriptional effectors associated with mRNAs, circular RNAs (circRNAs), and noncoding RNAs by developing in vivo crosslinkingcoupled RNA affinity purification methods to purify endogenous RNPs. Our recent studies revealed mechanistic changes in G0: uncovering inhibition of conventional translation and its replacement by noncanonical mechanisms that enable specific gene expression in G0 to elicit chemoresistance. These specialized mechanisms are driven by modifications of mRNAs, associated regulator RNAs and proteins, and ribosomes, which are induced in G0- and chemotherapy-induced signaling. These investigations reveal gene expression control by RNA regulators and non-canonical translation mechanisms that cause tumor persistence. Based on our data demonstrating altered RNPs, modifications, and specific translation in G0, we propose that transiently quiescent, chemoresistant subpopulations in cancers are maintained by specialized post-transcriptional mechanisms that permit selective gene expression, necessary for chemotherapy survival and tumor persistence.
The primary goal of our research is to characterize the specialized gene expression program in quiescent, chemoresistant cancers, and its underlying posttranscriptional and translational regulators that contribute to G0 and tumor persistence. A concurrent focus is to investigate RNA modifications and mechanisms of noncoding RNAs, RNPs, and ribosomes in G0 that contribute to chemoresistance, using cancer cell lines, in vivo models, patient samples, and stem cells. An important direction is to identify unique RNA markers and develop novel therapeutic approaches that block or utilize disease-specific RNA mechanisms such as block with inhibitors or antisense, or use selective translation as mRNA and circRNA therapeutics, of targets that encode for critical immune and tumor survival regulators—and thereby curtail chemoresistance.
The lab has four core directions:
Selected Publications
Datta C, Truesdell SS, Wu KQ, Bukhari SIA, Ngue H, Buchanan B, Le Tonqueze O, Lee S, Kollu S, Granovetter MA, Boukhali M, Kreuzer J, Batool MS, Balaj L, Haas W, Vasudevan S. Ribosome changes reprogram translation for chemosurvival in G0 leukemic cells. Sci Adv 2022; 8:eabo1304.
Lee S, Micalizzi D, Truesdell SS, Bukhari SIA, Boukhali M, Lombardi-Story J, Kato Y, Choo MK, Dey-Guha I, Ji F, Nicholson BT, Myers DT, Lee D, Mazzola MA, Raheja R, Langenbucher A, Haradhvala NJ, Lawrence MS, Gandhi R, Tiedje C, Diaz-Muñoz MD, Sweetser DA, Sadreyev R, Sykes D, Haas W, Haber DA, Maheswaran S, Vasudevan S. A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells. Genome Biol 2020; 21:33.
Chen H, Yang H, Zhu X, Yadav T, Ouyang J, Truesdell SS, Tan J, Wang Y, Duan M, Wei L, Zou L, Levine AS, Vasudevan S, Lan L. mC modification of mRNA serves a DNA damage code to promote homologous recombination. Nat Commun 2020; 11:2834.
Li B, Clohisey SM, Chia BS, Wang B, Cui A, Eisenhaure T, Schweitzer LD, Hoover P, Parkinson NJ, Nachshon A, Smith N, Regan T, Farr D, Gutmann MU, Bukhari SI, Law A, Sangesland M, Gat-Viks I, Digard P, Vasudevan S, Lingwood D, Dockrell DH, Doench JG, Baillie JK, Hacohen N. Genome-wide CRISPR screen identifies host dependency factors for influenza A virus infection. Nat Commun 2020; 11:164.
Ebright RY, Lee S, Wittner BS, Niederhoffer KL, Nicholson BT, Bardia A, Truesdell S, Wiley DF, Wesley B, Li S, Mai A, Aceto N, Vincent-Jordan N, Szabolcs A, Chirn B, Kreuzer J, Comaills V, Kalinich M, Haas W, Ting DT, Toner M, Vasudevan S, Haber DA, Maheswaran S, Micalizzi DS. Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis. Science 2020; 367:1468-1473.
Bukhari SI, Truesdell, SS, J, Lee, S, Kollu, S, Classon, A, Boukhali, M, Jain, E, Mortensen, RD, Yanagiya, A, Sadreyev, RI, Haas, W, and Vasudevan, S. (2016). A specialized mechanism of translation mediated by FXR1a-associated microRNP in cellular quiescence. Molecular Cell. 61(5):760-773.
Year | Degree | Institution |
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2003 | PhD | University of Medicine and Dentistry of New Jersey |
1995 | BSc | Bangalore University |
Research Fellow | Yale University School of Medicine, Yale | 2003-2009 | New Haven, Connecticut, United States |
PhD | Rutgers-UMDNJ, Microbiology and Molecular Genetics | 1997-2003 |
2024-RNA Society Award for Excellence in Inclusive Leadership
2013-The Leukemia and Lymphoma Society New Idea Award
2010-Ryder Strategic Innovator Award for Medical Research/ECOR
2010-The Smith Family Awards Program for Excellence in Biomedical Research
2009-RNA Society Scaringe Award
2009-Leukemia Research Foundation Award
2009-Cancer Research Institute Investigator Award
2009-The V Foundation for Cancer Research Scholar Award
2008-The Leukemia and Lymphoma Society Special Fellowship
2008-New York Academy of Sciences Blavatnik Award Finalist
2004-Cancer Research Institute postdoctoral Fellowship
July, 2009-Jan, 2019 Assistant Professor, Dept. of Medicine, Harvard Medical School, Boston, MA
July, 2009-Jan, 2019 Assistant Geneticist, Cancer Center, Massachusetts General Hospital, Boston, MA
Feb, 2019-June, 2024 Associate Investigator, Cancer Center, Massachusetts General Hospital, Boston, MA
July, 2009-June, 2024 Associate Investigator, Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
Feb, 2019-current Associate Professor, Dept. of Medicine, Harvard Medical School, Boston, MA
Jan, 2013-current Principal Faculty, Harvard Stem Cell Institute, Harvard University, Boston, MA
Sept, 2019-current Faculty, HMS Initiative for RNA Medicine Harvard Medical School, Boston, MA
June, 2020-current Faculty member, Dana Farber/Harvard Cancer Center, Boston MA
May, 2023-current Affiliate Faculty, Broad Institute, Cambridge, MA
March, 2024-current Director of Technology and Innovation, Associate Professor (research), Brown RNA Center, Brown University, Providence, RI