ASSISTANT PROFESSOR, BIOCHEMISTRY AND MOLECULAR BIOLOGY
Ph.D., Madras University, INDIA, 2005
Research Interest: Characterization of cancer stem cells, Mucins in ovarian cancer
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.
1. Vaz A, Ponnusamy MP, Seshacharyulu P, and Batra. S.K. Advances on pancreatic cancer stem cells for prognosis and therapy. Journal of Cancer Stem Cell Research 2014, 2:e1004.
2.Ponnusamy MP*, Vaz A*, Rachagani S, Dey P, Ganti AK, and Batra. Role of RNA Polymerase II Associated Factor 1 (Paf1/PD2) in Facilitating Drug Resistance of Cancer Stem Cells: A Novel Cancer Stem Cell Maintenance Marker. British Journal of Cancer, 2014 (Epub ahead of print).
3. Ponnusamy MP, Seshacharyulu P, Lakshmanan I, Vaz AP, Chugh S, Batra SK. Emerging Role of Mucins for Epithelial to Mesenchymal Transition. Curr Cancer Drug Targets. 2013, 13(9): 945-56.
4. Vaz AP, Ponnusamy MP and Batra SK. Cancer Stem Cells and Therapeutic Targets: An Emerging Field for Cancer Treatment. Drug Deliv Transl Res. 2013, 3(2):113-120.
5. Pandey P*, Seshacharyulu P*, Das S, Rachagani S, Ponnusamy MP, Yan Y, Johansson SL, Datta K, Lin ML and Batra SK. Impaired expression of protein phosphatase 2A subunits enhances metastatic potential of human prostate cancer cells through activation of AKT pathway. British Journal of Cancer. 2013,108(12):2590-600.
6. Macha MA, Rachagani S, Gupta S, Pai P, Ponnusamy MP, Batra SK, Jain M. Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling. Cancer Lett. 2013, 341(2):166-77.
7. Jain M, Gupta S, Kaur S, Ponnusamy MP, Batra SK. Emerging Trends for Radioimmunotherapy in Solid Tumors. Cancer Biother Radiopharm. 2013,28(9):639-650.
8. Mukhopadhyay P, Lakshmanan I, Ponnusamy MP, Chakraborty S, Jain M, Pai P, Smith LM, Lele SM, Batra SK. MUC4 Overexpression Augments Cell Migration and Metastasis through EGFR Family Proteins in Triple Negative Breast Cancer Cells. PLoS One. 2013, 8(2):e54455.
9. Majhi PD, Lakshmanan I, Ponnusamy MP, Jain M, Das S, Kaur S, Shimizu ST, West WW, Johansson SL, Smith LM, Yu F, Rolle CE, Sharma P, Carey GB, Batra SK, Ganti AK. Pathobiological Implications of MUC4 in Non-Small-Cell Lung Cancer. J Thorac Oncol.2013, 8(4):398-407.
10. Rachagani S, Torres MP, Kumar S, Haridas D, Baine M, Macha M, Kaur S, Ponnusamy MP, Dey P, Johansson SL, Jain M, Wagner KU and Batra SK. Mucin expression profile in the progression of pancreatic cancer in the KrasG12D transgenic mouse model. J. Hematol. Oncol. 2012, 5:68.
11. Rachagani S, Ponnusamy MP*, Macha MA* and Batra SK. MUC4 potentiates invasion and metastasis of pancreatic cancer cells through stabilization of fibroblast growth factor receptor 1 (FGFR1). Carcinogenesis 2012, 33(10):1953-64.
12. Momi N, Kaur S, Ponnusamy MP, Kumar S, Wittel WA and Batra SK. Interplay Between Smoking-induced Genotoxicity and Altered Signaling in Pancreatic Carcinogenesis. Carcinogenesis 2012, 33(9):1617-28.
13. *Ponnusamy MP, *Momi N, Kunigal S, Chellappan S and Batra SK. Nicotine up-regulates MUC4 mucin via α7 nicotinic acetylcholine receptor and JAK2/STAT3 signaling cascade. Oncogene 2013, 32(11):1384-95.
14. Kunigal S, Ponnusamy MP, Momi N, Batra SK and Chellappan SP. Nicotine, IFN-γ and retinoic acid mediated induction of MUC4 in pancreatic cancer cells involve E2F1 and STAT-1 transcription factors and multiple signaling cascades. Molecular Cancer 2012, 11(1):24.
15. *Ponnusamy MP, *Seshacharyulu P, Haridas D, Jain M, Ganti AK and Batra SK. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012, 16(1):15-31
16. Dey P, Ponnusamy MP, Deb S and Batra SK. Human RNA Polymerase II-Association Factor 1 (hPaf1/PD2) Interacts and Facilitates Nuclear Import of Chromatin Remodeling Protein CHD1 in Pancreatic Cancer cells. PLoS One. 2011, 6(10): e26926.
17. Ponnusamy MP, Seshacharyulu P, Vaz A, Dey P and Batra SK. MUC4 Stabilizes HER2 Expression and Maintains the Cancer Stem Cell Population in Ovarian Cancer Cells. J. Ovarian Res. 2011, 4(1): 7.
18. Haridas D, Chakraborty S, Ponnusamy MP, Lakshmanan I, Rachagani S, Cruz E, Kumar S, Das S, Lele SM, Anderson JM, Wittel WA, Hollingsworth MA and Batra SK. Pathobiological Implications of MUC16 Expression in Pancreatic Cancer. PLoS One. 2011, 6(10): e26839.
19. Lakshmanan I, Ponnusamy MP, Das S, Chakraborty S, Haridas D, Mukhopadhyay P, Lele SM and Batra SK. MUC16 induced rapid G2/M transition via interactions with Jak2 for increased proliferation and anti-apoptosis in breast cancer cells. Oncogene. 2012, 31(7): 805-17
20. Mukhopadhyay P, Chakraborty S, Ponnusamy MP, Lakshmanan I, Jain M and Batra SK. Mucins in the Pathogenesis of Breast Cancer: Implications in Diagnosis, Prognosis and Therapy. BBA-Reviews on Cancer. 2011, 1815(2): 224-40.
21. Rachagani S, Senapati S, Chakraborty S, Ponnusamy MP, Kumar S, Smith LM, 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. 2011, 104(6): 1038-48.
22. Ponnusamy MP. Stem Cell Research and Cancer Stem Cells. Editorial. J. Tissue Sci. Eng, 2011, 2:3.
23. Ponnusamy MP, Lakshmanan I, Jain M, Das S, Chakraborty S, Dey P and Batra SK. MUC4 induced epithelial to mesenchymal transition: a novel mechanism for human ovarian cancer metastasis. Oncogene. 2010, 29(42): 5741-54.
24. Torres MP, Ponnusamy MP, Chakraborty S, Smith LM, Das S, Arafat HA and Batra SK. Effects of thymoquinone in the expression of MUC4 in pancreatic cancer cells: implications for the development of cancer therapies. Mol. Can. Therapeutics. 2010, 9(5): 1419-31.
25. *Ponnusamy MP, *Torres MP Lakshmanan I and Batra SK. Immunopathogenesis of ovarian cancer. Minerva Med. 2009, 100(5): 385-400.
26. Ponnusamy MP, Deb S, Dey P, Chakraborty S, Rachagani S, Senapati S and Batra SK. RNA Polymerase II-Association Factor 1 (Paf1/PD2) maintains self-renewal by its interaction with Oct3/4 in mouse embryonic stem cells. Stem Cells. 2009, 27(12): 3001-11.
27. Ponnusamy MP, Singh, A.P., Jain M, Chakraborty S, Moniaux N and Batra SK. MUC4 mucin activates HER2 signaling and enhances the motility of human ovarian cancer cells. British Journal of Cancer. 2008, 99(3): 520-526.
28. *Ponnusamy MP, *Deb S, Senapati S, Dey P and Batra SK. (2008) Human PAF Complexes in Endocrine Tumors. Expert Rev. Endocrinol. Metab. 2008, 3(5): 557-565.
29. Deb S, Ponnusamy PM and Batra SK. Paf1 (RNA Polymerase II Associated Factor, homolog (S. cerevisiae). Atlas of Genetics and Cytogenetics in Oncology and Haematology. 2008.
30. Ponnusamy MP and Batra SK. Ovarian Cancer: Emerging concept on cancer stem cells. J. Ovarian Res. 2008, 1(1): 4.
31. *Singh AP, *Senapati S, Ponnusamy MP, Jain M, Lele SM, Davis JS, Remmenga S and Batra SK. The clinical potential of mucins in diagnosis, prognosis and therapy of ovarian cancer. Lancet Oncology. 2008, 11: 1076-85.
32. *Ponnusamy MP, *Deb S, Senapati S, Dey P and Batra SK. (2008) Human PAF Complexes in Endocrine Tumors. Expert Rev. Endocrinol. Metab. 2008; 3(5): 557-565.
33. *Chaudary K, *Deb S, Moniaux N, Ponnusamy MP and Batra SK. Human RNA Polymerase II Association Factor (hPAF) complex dysregulation in Cancer. Oncogene. 2007, 26(54): 7499-507.
34. Andrianifahanana M,Ponnusamy MP*, Singh AP*, Nemos C*, Moniaux N, Varshney GC, Mehta PP, and Batra SK. IFN-γ- induced expression of muc4 in pancreatic cancer cells is mediated by stat-1 upregulation: a novel mechanism for IFN-γ response. Oncogene. 2007;26(51): 7251-61.
35. Senapati S, Ponnusamy PM, Singh AP, Jain M and Batra SK. MUC16 (mucin16, cell surface associated). Atlas of Genetics and Cytogenetics in Oncology and Haematology. 2007.
36. Ponnusamy MP, Venkatraman G, Singh AP, Chauhan SC, Johansson SL, Jain M, Smith LM, Davis JS, Remmenga SW and Batra SK. Expression of TAG-72 in ovarian cancer and its correlation with tumor stage and patient prognosis. Cancer Letters. 2007, 251: 247-257
37. Moorthy PP, Anand Kumar A and Devaraj H. Expression of Gas7 gene and Oct4 in the Embryonic Stem Cells of the mice. Stem Cells Dev. 2005, 14 (6): 664-70.
Title: hPaf1 as a novel drug resistance marker for ovarian cancer stem cells (2013-1014)
From Elsa U Pardee Foundation
Junior Faculty award
PI: Moorthy P. Ponnusamy
Title: PD2/Paf1 and pancreatic cancer stem cells (2014-2017)
K22-Transition Career Development Award from NCI
PI: Moorthy P. Ponnusamy
Surinder K. Batra
William G. Chaney
G. Stanley Cox
Richard G. MacDonald
Parmender P. Mehta
Robert F. Ramaley