185 Cambridge Street
Boston, MA 02114
Shobha Vasudevan, PhD
Associate Professor of Medicine
Harvard Medical School
Krantz Family Center for Cancer Research
Center for Regenerative Medicine
Explore the Vasudevan Lab
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 posttranscriptional mechanisms are altered, with modification of noncoding RNAs, associated complexes and ribosomes. These control vital genes in cancer and are important for chemoresistance and 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.
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 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 G0-specific RNA markers and develop novel therapeutic approaches to block selective translation in G0, of targets that encode for critical immune and tumor survival regulators—and thereby curtail chemoresistance.
The lab has four core directions:
- To characterize microRNAs and noncoding RNAs, and their cofactors that control the expression of tumor survival regulators, using in vivo biochemical purification methods.
- To investigate the mechanisms of posttranscriptional and translational regulation by noncoding RNAs, RNPs, and ribosome regulators.
- To elucidate the modification and regulation of key mRNAs and ribosomes, by G0- and chemotherapy-induced signaling.
- To develop therapeutic approaches that interfere with selective translation, and manipulate interactions of noncoding RNAs with targets that encode for critical tumor survival regulators. These studies should lead to a greater understanding of the versatile role of post-transcriptional mechanisms in cancer persistence and to novel approaches in RNA-based therapeutics.
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.
Shobha Vasudevan, PhD
Dr. Vasudevan is Associate Professor of Medicine at Harvard Medical School, Principal Investigator at the Center for Cancer Research, Massachusetts General Hospital (MGH), faculty member at the Center for Regenerative Medicine, and Principal Faculty at Harvard Stem Cell Institute. Her research is focused on the role of noncoding RNAs and translation mechanisms underlying clinically resistant cancers and cancer quiescence, as a basis for designing new therapies. Her laboratory uncovered that quiescent cells use specialized post-transcriptional and translational mechanisms, with distinct regulatory mechanisms and RNAs that promote gene expression important for cancer persistence. Dr. Vasudevan completed her postdoctoral fellowship in the laboratory of Dr. Joan A. Steitz at Yale University. She received her doctorate in the laboratory of Dr. Stuart W. Peltz at Rutgers University-UMDNJ.
The Vasudevan lab is currently focused on investigating post-transcriptional mechanisms responsible for gene expression regulation in drug resistant cancer cells, with an emphasis “on understanding and targeting RNA mechanism changes in cancer states that are clinically resistant, such as quiescent cancer cells”.
Chandreyee received her Bachelor’s in Science (Chemistry) from St. Xavier’s College Kolkata, and Masters in Chemistry from Indian Institute of Technology (IIT), Kharagpur, India. She earned her PhD in Biochemistry from Indian Institute of Science (IISc), Bangalore, Karnataka India. Her thesis was focused on the study of Nucleoid Associated proteins and DNA topology mediated gene regulation in Mycobacterium tuberculosis. In the Vasudevan lab, Chandreyee’s research is focused on mechanism of non-canonical translation and ribosome-mediated gene expression regulation.
Jitendra received his B.S. in microbiology from, Tribhuvan University, Kathmandu, Nepal in 2010. He obtained his M.A. in Sociology and M.S. in Medical Microbiology from Tribhuvan University, respectively, in 2015 and 2017. For his graduate thesis, he focused on the study of intestinal parasite infestation among schoolchildren of Kathmandu. He conducted ethnographic study on the "Baram" tribe of Gorkha Nepal for the social science. He earned his PhD in cancer biology from College of Pharmacy, Mokpo National University in South Korea in 2022. His Ph.D. work was funded by National Research Foundation of Korea (NRF), focused on the development of Sphingosine Kinase inhibitors and their anticancer role on human pancreatic and colorectal cancer. Jitendra joined Vasudevan Lab as a postdoctoral researcher in July 2022.
His current research focuses on the role of circular RNA and extracellular vesicles in the emergence of a drug-resistant cancer subpopulation. He also examines how these components interact with survival regulators with the aim to target them to develop anticancer therapeutics.
Ruby received Bachelor’s in Pharmacy from Purbanchal University and Master’s in Pharmacy from Kathmandu University, Nepal. She earned her PhD in Pharmacy from Seoul National University, South Korea in 2021. Her thesis was focused on the study of metronomic chemotherapy for anti-angiogenesis and immunomodulation. In Vasudevan’s lab, she will be doing research in mechanism of immune evasion by quiescent cancer cells.
My name is Zeeba Kamaliyan, a recent PhD graduate of Medical Genetics from Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran. I earned my B.Sc. in Molecular and cellular Biology and my M.Sc. in Human Genetics consecutively, in 2013 and 2016. From my early days in the field of genetics, I was attracted to the concept of non-coding RNAs and their role in genetic diseases. For my master’s thesis, I studied the role of some genes and polymorphisms involved in piRNA pathway in male infertility. As I started my PhD, I had a close encounter with breast cancer in my family and became more aware of cancer complexity and prevalence in today’s world. During the last five years, I tried my best in conducting and collaborating in cancer-related projects, including my PhD thesis, which focused on investigating the specific oncoregulators and their associated long non-coding RNAs (lncRNAs) involved in aggressiveness of triple-negative breast cancer.
I am currently very enthusiastic to apply my skills, experience and passion for molecular genetics and cancer biology in a research career, to help find new therapeutic strategies for cancer. On the other hand, when I am not busy with research and lab works, you can find me painting or most definitely hiking in nature. I will join Vasudevan Lab as a research fellow soon, and I am very excited to work with this incredible team.
Harrison is a 4th-year undergraduate at Harvard College from Los Angeles, CA who is studying biomedical engineering with a minor in the history of science. During his time in the Vasudevan Lab, Harrison has studied the role of ribosomal proteins in quiescent and chemotherapy resistance in acute myeloid leukemia. His current research focuses on extracellular vesicles and circular RNAs in causing chemoresistance in breast cancer. In his spare time, Harrison enjoys playing and watching basketball, learning trivia, exploring Boston, and making science animations!
Sadia is a student on the pre-medical track in Harvard College’s Class of 2023. She concentrates in Molecular and Cellular Biology with a secondary in Ethnicity, Migration, and Rights. At the Vasudevan Lab, she studies how metabolic pathways regulate RNA methylation and translation mechanisms in chemoresistant cancer cells. In her free time, she enjoys reading books, watching horror movies, biking, and exploring new places with her friends!
Fadzai is a junior at Harvard College studying Molecular & Cellular Biology with a citation in French. She was born in Harare, Zimbabwe, but grew up in Gqeberha, South Africa. At Harvard, she is involved with the Catholic Students' Association, dances on the Harvard Ballroom Dance Team, volunteers at the Harvard Square Homeless Shelter and provides tutoring for other students. In her free time, she enjoys playing the piano, reading books, doing art and watching Netflix. At the Vasudevan lab, she does research on the role of different proteins in promoting chemoresistance in cancer cells.
Alli is a junior at Harvard College studying Molecular and Cellular Biology with a secondary in Social Anthropology. She is originally from Reading, Massachusetts, and hopes to pursue a career that involves the intersection of molecular biology, public health, and medical anthropology. At Harvard, she is involved with the Foundation for the International Medical Relief of Children and Project Sunshine, two organizations that volunteer to help children in need. She is also a member of the Harvard Club Swim Team and Winthrop House Committee.
At the Vasudevan Lab, Alli is studying the role of extracellular vesicles in promoting tumor progression and survival. She plans to write her thesis on this topic in 2023-2024.
- Chandryee Datta, PhD (Postdoctoral Researcher)
- Jitendra Shrestha, PhD (Postdoctoral Researcher)
- Ruby Maharjan, PhD (Postdoctoral Researcher)
- Zeeba Kamaliyan, PhD (Postdoctoral Researcher)
- Alli Tompkins (Undergraduate Researcher)
- Harrison Ngue (Undergraduate Researcher)
- Sadia Laisa (Undergraduate Researcher)
- Fadzai Ngwerume (Undergraduate Researcher)
- Sooncheol Lee, PhD (Postdoctoral Researcher)
- Syed I. A. Bukhari, PhD (Instructor)
- Samuel S. Truesdell, M.tech (Lab manager)
- Wu Keith Qi, PhD (Lab manager)
- Hey-Jin Kim, PhD (Postdoctoral Researcher)
- Pritha Choudhury, PhD (Postdoctoral Researcher)