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Research at Mass General
Read the Vasudevan Lab 2017-2018 Annual Report
Shobha Vasudevan, PhDAssociate Professor of MedicineHarvard Medical School
Assistant in GeneticsMassachusetts General Hospital
The Vasudevan laboratory focuses on the role of post-transcriptional mechanisms in clinically resistant quiescent cancer cells. Tumors demonstrate heterogeneity, harboring a small subpopulation that switch from rapid proliferation to a specialized, reversibly arrested state of quiescence that decreases their susceptibility to chemotherapy. Quiescent cancer cells resist conventional therapeutics and lead to tumor persistence, resuming cancerous growth upon chemotherapy removal. Our data revealed that post-transcriptional mechanisms are altered, with modification of noncoding RNAs, associated complexes and ribosomes—molecules that control vital genes in cancer—which are important for the persistence of quiescent cancer cells.
The primary goal of our research is to characterize the specialized gene expression and their post-transcriptional regulators that underlie persistence of resistant cancer cells. A complementary focus is to investigate the modification of post-transcriptional regulators and their mechanisms in response to quiescent conditions and chemotherapy-induced signaling. Our goal is to develop a comprehensive understanding of the versatile roles of regulatory RNAs in cancer as a basis for early detection of refractory cancers and for designing new therapies.
Shobha Vasudevan, PhDPrincipal Investigator
Cells that survive clinical therapy include quiescent (G0) cells, observed as a clinically relevant population in leukemias and in several solid tumors associated with poor survival. G0 is a unique, nonproliferative phase that provides an advantageous escape from harsh situations and chemotherapy, allowing cells to evade permanent outcomes of senescence, differentiation, and apoptosisin tumor-negative 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 RNAs required for survival. Quiescence regulators and their expression that maintain the quiescent, chemoresistant state remain largely undiscovered despite the significance of G0 in cancers.
Our studies revealed that specific post-transcriptional regulators, including AU-rich elements (AREs), microRNAs, RNA-protein complexes (RNPs), ribosome factors and their 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, immune 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 and noncoding RNAs by developing an in vivo crosslinking-coupled affinity purification method to purify endogenous RNPs. Our recent studies have defined some of the mechanisms in G0: uncovering inhibition of conventional translation and its replacement by non-canonical post-transcriptional and translational 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-canonicaltranslation mechanisms that cause tumor persistence. Based on our data demonstrating noncoding RNP modifications and functions, and specific translation in G0, we propose that G0 chemoresistant populations in cancers are maintained by specialized gene expression—mediated by modified post-transcriptional mechanisms, necessary for persistence of the quiescent, chemoresistant state.
The primary goal of our research is to characterize the specialized gene expression program in quiescent chemo resistant cancers and its underlying post-transcriptional and translational regulators that contribute to G0 and tumor persistence. A concurrent focus is to investigate the modifications and mechanisms of noncoding RNAs, RNPs, and ribosomes in G0 that contribute to chemoresistance, using cancer cell lines, patient samples, and stem cells. An important direction is to identify unique G0-specific RNA markers and develop novel therapeutic approaches to block selective translation in G0, and interfere with noncoding RNAs and their targets that encode for critical immune and G0 regulators—and thereby curtail chemoresistance and cancer persistence.
The lab has four core directions:
1. To characterize microRNAs and noncoding RNAs, and identify their associated cofactors and targets that control expression of clinically important cytokines, cancer and cell state regulators, using in vivo biochemical purification methods.
2. To investigate the mechanisms of post-transcriptional and translational regulation by noncoding RNAs, RNPs, and ribosome regulators.
3. To elucidate the modification and regulation of function of noncoding RNAs, AREs, RNPs and ribosomes, and their modifiers, by G0- and chemotherapy-induced signaling.
4. To develop therapeutic approaches that interfere with select translation start sites and translation regulators, and manipulate interactions of noncoding RNAs with targets that encode for critical cancer cell survival regulators. These studies should lead to a greater understanding of the versatile role of RNA mechanisms in the persistence of cancers and to novel approaches in RNA-based therapeutics.
View a list of publications by researchers at the Vasudevan Laboratory
Bukhari SI, and Vasudevan, S. FXR1-associated microRNP: A driver of specialized, non-canonical translation in quiescent conditions. RNA Biology.14(2):137-145. doi: 10.1080/15476286.2016.1265197 (2017).
Martinez I, Hayes, K, Barr, J, Harold, A, Xie, M, Bukhari, SIA, Vasudevan, S, Steitz, JA, DiMaio, D. An exportin-1 dependent microRNA biogenesis pathway during human cell quiescence. PNAS. 2017;114(25):E4961-E4970. doi:10.1073/pnas.1618732114
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.
Lee S, Truesdell SS, Bukhari SIA, Lee JH, LeTonqueze O and Vasudevan S. Upregulation of eIF5B controls cell cycle arrest and speciﬁc developmental stages. PNAS, 2014 111(41):E4315-22.
Liu M, Roth A, Yu M, Morris R, Bersani F, Rivera MN, Lu J, Shioda T, Vasudevan S, Ramaswamy S, Maheswaran S, Diederichs S, Haber DA. The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis. Genes & Dev: 27(23):2543-8, 2013.
Chen A-J, Paik J-H, Zhang H, Shukla SA, Mortensen RD, Hu J, Ying H, Hu B, Hurt J, Farny N, Dong C, Xiao Y, Wang YA, Silver PA, Chin L, Vasudevan S and DePinho RA. Star RNA-binding protein, Quaking, suppresses cancer via stabilization of speciﬁc miRNA. Genes Dev. 26(13):1459-72, 2012.
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