Shobha VASUDEVAN

RESEARCH

Our 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 tumors to resist therapies and anti-tumor immunity, enabling 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 we target to improve patient survival. Based on our studies, we utilize RNA mechanism inhibitors to block such unique, survival adaptations, to limit tumor persistence. 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.

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 RNA-protein complexes (RNPs). Our recent studies revealed mechanistic changes in G0: uncovering inhibition of conventional translation and its replacement by noncanonical mechanisms that promote specific gene expression in G0 to elicit chemoresistance. These specialized mechanisms, including specific post-transcriptional regulators, are driven by modifications of mRNAs, associated regulator noncoding RNAs and RNPs, and ribosomes, which are induced by 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. We 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.

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 deep learning 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.

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 develop computational 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

Zhou, P, Li, Z, Liu, F, Kwon, F, Hsieh, T-C, Ye, S, Vasudevan, S, Lee, J-Ae, Zhou, C. BAMBI: Integrative biostatistical and artificial-intelligence models discover coding and non-coding RNA genes as biomarkers. Briefings in Bioinformatics. 2025; 26(2):bbaf073. doi: 10.1093/bib/bbaf073.

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.