ASSISTANT PROFESSOR, BIOCHEMISTRY AND MOLECULAR BIOLOGY
Ph.D., Madras University, INDIA, 2005
Research Interest: Mucins in Ovarian Cancer; Cancer Stem Cells.
Biochemical and Molecular Studies of MUC4 in Ovarian Cancer: Ovarian cancer is a highly lethal disease which represents a great clinical challenge in gynecologic oncology. It is asymptomatic until the disease is in the late stage, causing it to have the highest fatality-to-case ratio of all gynecologic malignancies. It is essential to analyze the diagnostic and prognostic markers for ovarian cancer to manage this lethal disease. My first goal is to analyze the role and mechanism of membrane bound mucins (MUC4 and MUC16) in the progression of ovarian cancer. We have recently shown that MUC4 plays a major role in ovarian cancer cell motility and metastasis, in part, by altering actin arrangement and potentiating HER2 downstream signaling in these cells. In addition, we have identified that MUC4 plays a role in inducing epithelial-mesenchymal transition (EMT) in ovarian cancer cells. This occurs through an upregulation of N-cadherin expression that leads to enhanced metastatic potential of human ovarian cancer cells.
Further, based on our observations that MUC4 interacts with and stabilizes the receptor tyrosine kinase ErbB2 (HER2), we have hypothesized that the interaction between MUC4 and HER2 could be at least partly responsible for resistance of HER2 expressing breast cancers to Trastuzumab (Herceptin). This project is to investigate the role of MUC4 in resistance of breast cancer cells to Trastuzumab and identify the underlying mechanism. This project explores an innovative approach to tackle Trastuzumab resistance by targeting MUC4 in combination with ErbB2, which should provide a synergistic outcome by unmasking the epitope (masked by MUC4) and thus potentially improve outcome for breast cancer patients.
We have recently demonstrated that MUC4 overexpression leads to an enriched ovarian cancer stem cell population either directly or indirectly through HER2. Further we are investigating the biological consequence and drug resistance property of MUC4-mediated stabilization of HER2 in ovarian cancer stem cells and its effect on the pathogenesis of ovarian cancer. In future, this study would be helpful for MUC4-directed therapy for the ovarian cancer stem cell population.
Role and Mechanism of hPaf1/PD2 in Cancer Stem Cells: My second goal is to identify and characterize the cancer stem cell populations in different cancers. Over the last several years, it has been identified that a small population (less than 5%) of cancer cells, referred as “Cancer Stem Cells (CSCs)” or “side population cells (SP)”, is responsible for the aggressiveness, metastasis and resistance of ovarian cancer cells to therapy. Based on our previous study on role of human polymerase association factor 1/pancreatic differentiation 2 (hPaf1/PD2) in the maintenance of self-renewal in mouse embryonic stem cells, I hypothesize that hPaf1/PD2 may play a role in regulating self-renewal of CSCs. This project seeks to investigate the role and mechanism of a novel molecule hPaf1/PD2 in cancer stem cells. The identification of cancer stem cell specific marker hPaf1/PD2 and its role in CSC maintenance would provide extremely important information that is critical in advancing towards the long-term goal of developing novel therapeutic strategies for cancer stem cell population.
Kunigal S, Ponnusamy MP, Momi N, Batra SK and Chellappan SP. Nicotine, IFN-gamma and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades. Molecular Cancer 11(1):24, 2012.
Lakshmanan I, Ponnusamy M.P, Das S, Chakraborty S, Haridas D., Mukhopadhyay P, Lele S.M and Batra S.K. MUC16 Induced Rapid G2/M Transition via Interaction with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells. Oncogene, 31(7):805-17, 2012.
Seshacharyulu,P, Ponnusamy, MP, Haridas, D, Jain, M, Ganti A.K and Batra S.K. Targeting the EGFR signaling pathway in cancer therapy. Expert Opinions on Therapeutic Targets, 16, 15-31, 2012.
Dey P, Ponnusamy, MP., Deb, S and Batra SK. Human RNA Polymerase II-Association Factor 1 (hPaf1/PD2) Regulates Histone Methylation and Chromatin Remodeling in Pancreatic Cancer. PLoS One 6(10):e26926, 2011.
Haridas D, Chakraborty S, Ponnusamy MP, Lakshmanan I, Rachagani S, Cruz E, Kumar S, Das S, Lele SM, Anderson JM, Wittel UA, Hollingsworth MA, and Batra S.K. Pathobiological implications of MUC16 expression in pancreatic cancer. PLoS One, 6(10), e26839, 2011.
Ponnusamy, M.P., Seshacharyulu P, Vaz A, Dey, P., and Batra S.K. MUC4 stabilizes HER2 expression and maintains the cancer stem cell populations in ovarian cancer cells. J. Ovarian Research, 4(1):7, 2011.
Mukhopadhyay, P; Chakraborty, S, Ponnusamy, M.P., Lakshmanan, I., Jain, M. and Batra, S.K. Mucins in the pathogenesis of breast cancer: implications in diagnosis, prognosis and therapy. BBA Reviews on Cancer, 1815(2):224-240, 2011.
Rachagani S, Senapati S, Chakraborty S, Ponnusamy MP, Kumar S, Smith L.M, Jain M and Batra, SK. Activated KrasG12D associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherin. British Journal of Cancer, 104(6):1038-48, 2011.
Torres M.P., Ponnusamy M.P., Chakraborty S., Arafat H.A., Das S. and Batra S.K. Effects of thymoquinone in the expression of MUC4 in pancreatic cancer cells: implications for the development of cancer therapies. Molecular Cancer Therapeutics, 9(5):1419-31, 2010
Ponnusamy, M.P., Lakshmanan, I., Jain, M., Das, S., Chakraborty, S., Dey, P., and Batra S.K. MUC4 mucin induced epithelial to mesenchymal transition: a novel mechanism for metastasis of human ovarian cancer cells. Oncogene, 29(42):5741-54, 2010.
Torres,M.P., Ponnusamy,M.P., Lakshmanan,I. and Batra,S.K. Immunopathogenesis of ovarian cancer. Minerva Med., 100: 385-400, 2009.
Ponnusamy,M.P., Deb,S., Dey,P., Chakraborty,S., Rachagani,S., Senapati,S. and Batra,S.K. RNA Polymerase II Associated Factor 1/PD2 Maintains Self-Renewal by Its Interaction with Oct3/4 in Mouse Embryonic Stem Cells, Stem Cells., 27: 3001-3011, 2009.
Singh, A.P., Shantibusan S., Ponnusamy. M.P., Jain, M., Lele, S.M., Davis J.S., Remmenga.S and Batra S.K. Clinical potential of mucins in diagnosis, prognosis and therapy of ovarian cancer. Lancet Oncology 9, 1076-1085, 2008.
Ponnusamy M.P and Batra S.K. Ovarian Cancer: Emerging concept on cancer stem cells. J. Ovarian Research, 1 (4), 1-8, 2008.
Deb S., Ponnusamy. M.P., Senapati, S., Dey, P and Batra, SK. Human PAF1 complexes I endocrine tumors and pancreatic cancer. Expert Reviews Endocrine Metabolism, 3(5), 557-565, 2008.
Ponnusamy, M.P, Singh, A.P., Jain M., and Batra, S.K. MUC4 mucin activates HER2 signaling and enhances the motility of human ovarian cancer cells. British Journal of Cancer, 99(3):520-6, 2008.
Deb S, Ponnusamy MP, and Batra SK. PAF1 (Paf1, RNA polymerase II associated factor, homolog (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol. September 2008.
Current Grants and Contracts
Title: hPaf1 in the drug resistance of ovarian cancer stem cells (2013-2014)
From Elsa U Pardee Foundation
Surinder K. Batra
William G. Chaney
G. Stanley Cox
Richard G. MacDonald
Parmender P. Mehta
Robert F. Ramaley