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Read the Vasudevan Lab 2017-2018 Annual Report
Shobha Vasudevan, PhDAssistant Professor of MedicineHarvard Medical School
Assistant in GeneticsMassachusetts General Hospital
The Vasudevan laboratory focuses on the role of noncoding RNAs in cancer. Tumors demonstrate heterogeneity, harboring a small proportion of assorted cells that switch from rapid proliferation—characteristic of other cancer cells—to a specialized, reversibly arrested state of quiescence that decreases their susceptibility to chemotherapy. Quiescent cancer cells can resist conventional therapeutics and contribute to cancer recurrence, resuming proliferation and cancerous growth upon chemotherapy removal. Our data revealed that microRNAs, noncoding RNAs that control vital genes in cancer and growth, are important for the persistence of quiescent cancer cells. The primary goal of our research program is to characterize the expression and roles of regulatory noncoding RNAs and AU-rich elements (AREs) in quiescence and tumor progression. A complementary focus is to investigate the regulation of noncoding RNAs and AREs in response to quiescent conditions in tumors, stem cells and germ cells. Our goal is to develop a greater understanding of the versatile roles of regulatory RNAs in cancer as a basis for designing new drug therapies.
Shobha Vasudevan, PhDPrincipal Investigator
AU-rich elements (AREs) are conserved mRNA 3’-untranslated region (UTR) regulatory elements while microRNAs are small noncoding RNAs that target distinct 3’UTR sites and control post-transcriptional gene expression of clinically relevant messages, including those of cytokines and growth factors. Their deregulation leads to a broad range of critical effects, including tumor growth, chemoresistance, metastasis, and immune and developmental disorders.
Studies indicate that 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 rates. G0 is a unique, nonproliferative phase that provides an advantageous escape from harsh situations and chemotherapy, allowing cells to evade permanent outcomes of tumor-negative environments such as senescence, differentiation and apoptosis. Instead, the cell is suspended reversibly in an assortment of transition phases that retain the ability to return to proliferation and contribute to tumor heterogeneity, resistance and recurrence. G0 demonstrates a switch to a distinct gene expression program, upregulating those mRNAs and regulatory RNAs— including microRNAs—required for survival and persistence. Quiescence regulatory factors and their expression that maintains the state remain largely undiscovered despite the signiﬁcance of G0 in cancers.
Our studies revealed that speciﬁc UTR elements such as AREs, microRNAs and their associated RNA-protein complexes (RNPs) are directed by such cellular conditions to alter expression patterns of distinct, clinically important genes. We identiﬁed post-transcriptional effectors associated with these mRNAs 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 the inhibition of conventional translation and its replacement by alternative mechanisms to enable speciﬁc gene expression in G0. These investigations have major implications for understanding gene expression control by potent RNA regulators and specialized translation mechanisms that contribute to tumor persistence. Based on our data demonstrating speciﬁc translation microRNA expression and functions in G0, we propose that G0 populations in cancers are maintained in part, by specialized gene expression mechanisms and altered expression and function of regulatory RNAs and targets, necessary for persistence of the quiescent state.
The primary goal of our research program is to investigate the underlying mechanisms of post-transcriptional and translational control of critical, cancer-associated genes, and the roles of regulatory noncoding RNAs, microRNAs, AREs, and their associated RNPs that contribute to quiescence and tumor persistence. A complementary focus is to investigate the regulation of noncoding RNAs, RNPs, and ribosomes in quiescence, using cancer cell lines, patient samples, stem cells and germ cells. An important direction is to identify unique G0 RNA markers and develop novel therapeutic approaches that block selective translation in G0, and interfere with non-coding RNAs and their targets that encode for critical immune and quiescence regulators, and thereby curtail cancer persistence and recurrence.
The lab has four core directions:
1. To characterize microRNAs and noncoding RNAs, and identify their as-sociated cofactors and target mRNAs that control expression of clinically important cytokines, cancer and cell state regulators, using previously developed in vivo biochemical puriﬁcation methods and assays.
2. To investigate the mechanisms of post-transcriptional and translational regulation by noncoding RNAs, RNPs, and ribosome regulators.
3. To elucidate the regulation of expression and function of noncoding RNAs, AREs, RNPs, and ribosomes by tumor-associated conditions.
4. To develop new therapeutic approaches that interfere with select translation start sites and translation regulators, and manipulate specific interactions of noncoding RNAs with their targets that encode for critical cell survival regulators in cancer. These studies should lead to a greater understanding of the versatile role of noncoding RNAs and translation mechanisms in the persistence of cancers and to novel approaches in RNA-based therapeutic applications.
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).
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.
Salony, Acha Sole X, Alves, CP, Dey-Guha I, Ritsma L, Boukhali M, Lee JH, Chowdhury J, Darp RA, Ken Ross K, Haas W, Vasudevan S, Ramaswamy S. (2016). AKT inhibition promotes non-autonomous cancer cell survival. Mol. Cancer Ther.,15(1):142-53. doi: 10.1158/1535-7163.MCT- 15-0414.
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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