The Vasudevan laboratory focuses on the role of post-transcriptional mechanisms in clinically resistant cancer cells, such as quiescent cancer cells, to develop effective therapeutics. 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. These control vital genes in cancer and are important for chemo-resistance and persistence of quiescent cancer cells. Quiescence is understudied and these hidden RNA mechanism changes that are induced by tumor stress conditions, are unexplored, but are unique vulnerabilities in refractory cancer cells that they target to improve patient survival. Based on our studies, we utilized RNA mechanism inhibitors to block such unique, survival adaptations, to limit tumor persistence. In accord, pre-treatment with such inhibitors followed by clinical therapy, reduces survival of a form of refractory leukemia, with implications for improved patient outcomes in refractory cancers. The primary goal of our research is to characterize the specialized post-transcriptional gene expression and their mechanisms that underlie persistence of resistant cancer cells. A complementary focus is to develop RNA-based therapeutics against these mechanisms and their regulation in response to quiescent conditions and chemotherapy-induced signaling. The overall objective of the Vasudevan lab is to comprehensively understand the versatile roles of RNA mechanisms in refractory cancer, for early detection of resistant tumors, and for translating these findings into new, effective therapies to limit tumor persistence.
 

Our research program focuses on uncovering and harnessing RNA usage mechanisms in resistant cancers to develop inducible, controlled RNA therapeutics. 

Apart from being part of the central dogma of the flow of genetic information, RNA is at its core, also a signaling molecule, which led to impactful Nobel Prize awarded discoveries and applications. In disease, there is inevitably a change in RNA usage or mechanisms that use RNA for protein synthesis, chemical modification, interaction, catalysis, structure, and location, as well as its signaling impact, all of which are understudied in disease and can be harnessed for therapeutics.

We study treatment resistant, persistent cancers to develop therapeutics to target this disease that impacts one of every two individuals in the world. Additionally, we learn from treatment resistant tumors on how to create effective therapeutics. This is because such tumors are, from the evolutionary perspective, incredibly successful survivors. Resistant tumors, when cornered and stressed by therapies and the immune system, not only reveal new RNA mechanisms that the cell is capable of but also precisely coordinate such mechanisms with multiple intra- and extracellular processes for their successful persistence. Learning and harnessing such mechanisms and their precise control will lead to effective naturally derived therapeutics.

There are four core directions of our research using cancer cell lines, in vivo models, and patient samples:

1. Uncover rules that govern survival mRNA expression due to RNA usage changes, such as translation frame, interactions, chemical changes, and RNA signaling in therapy-resistant cancer that have the most successful system for coordinated expression and cellular processes.
2. Characterize the regulation of and influence on the environment and cellular process that leads to precise co-ordination for tumor persistence for improved efficacy of RNA therapeutics.
3. Develop biochemical and computational methods and datasets to detect unexplored gene expression at the RNA usage level.
4. Harness our findings of regulatable mRNA and circRNA post-transcriptional mechanisms for targeted, inducible RNA therapeutics for immune programming and targeting therapy-resistant cancer, manipulate interactions of noncoding RNAs with targets that encode for disease regulators, and develop RNA applications for prophylaxis to prevent disease and its persistence.

 A primary research project studies Quiescent (G0) cancer cells. G0 cells are observed as a clinically relevant population in leukemias and other tumors associated with poor survival. G0 is a unique, non-proliferative phase that provides an advantageous escape from harsh situations like chemotherapy, allowing cells to evade permanent outcomes of senescence, differentiation, and apoptosis in such 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 non-coding RNAs required for survival. Quiescence regulators that maintain the quiescent, chemoresistant state remain largely undiscovered.

Our studies revealed that specific post-transcriptional 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 crosslinking-coupled 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. Weto characterize the specialized gene expression program in quiescent, chemoresistant cancers, and its underlying post-transcriptional and translational regulators that contribute to G0 and tumor persistence. We concurrently 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.

With the help of academic, clinical, industry collaborations and funding sources, we aim for three outputs: RNA usage and signaling mechanisms and their regulation and impact by the intra and extracellular environment; tools to investigate RNA mechanisms, and database resources on translatome and signaling integrated with existing cancer studies; Inducible, controlled RNA therapeutics based on our findings that are applicable for tumors and other disease. These studies should lead to a greater understanding of the versatile role of post-transcriptional mechanisms in disease persistence and to novel approaches in RNA-based therapeutics.

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.

Salony, Sole X, Alves CP, Dey-Guha I, Ritsma L, Boukhali M, Lee JH, Chowdhury J, Ross KN, Haas W, Vasudevan S, Ramaswamy S. (2016). AKT Inhibition Promotes Non-autonomous Cancer Cell Survival. Mol Cancer Ther 15(1):142-53.

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.

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

March, 2024-current Director of Technology and Innovation, Associate Professor (research), Brown RNA Center, Brown University, Providence, RI

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