Professor and Chairman, Biochemistry and Molecular Biology, Distinguished Helen Freytag Professor of Cancer Biology, Associate Director for Training and Education, Eppley Cancer Institute
Ph.D., NDRI (Kurukshetra Univ.), INDIA, 1983
Student research opportunities in my lab:
Medical students, summer research
Undergraduate students, summer research
Primary Research/Clinical Interests/Expertise:
Tumor-associated genes; cancer diagnostics, cancer vaccines; monoclonal antibodies, genetic engineering of antibodies
Tumor-associated Genes: Identification, Structure/Function Analysis, and Evaluation as Targets for Diagnosis/Therapy
The overall goals of our laboratory are to study the molecular mechanisms of neoplastic transformation, differentiation, and altered-growth in human pancreatic, ovarian and prostate tumors. Normal cell proliferation is under the intrinsic control of growth-promoting proto-oncogenes and growth-constraining anti-oncogenes.
Specifically, we are defining multifaceted roles of tumor associated antigens (MUC4 and PD2/hPaf1) in the pathogenesis of pancreatic, breast, ovarian and prostate cancers.
We cloned the full-length MUC4 cDNA (28 Kb) from human pancreatic tumor cDNA libraries and established its complete genomic organization (25 exons/introns over 100 kb) and expression profiles (Figure 1). Our studies have demonstrated the specific and differential expression of MUC4 in many cancers compared to normal tissues. Furthermore, using a MUC4-specific MAb generated in our laboratory, we showed that de novo expression of MUC4 is observed in precancerous pancreatic intraepithelial neoplasias (PanINs) and its expression increases progressively with the development of PC. These results were further confirmed in collaboration with investigators at University of California at San Francisco and University of Alabama. Notably, the overexpression of MUC4 is also associated with a poor prognosis for patients with PC. In multiple in-vitro and in-vivo studies, we have shown that the aberrant expression of MUC4 in PC results from diverse regulatory mechanisms.
MUC4 is a large-sized membrane-anchored glycoprotein. The size of the MUC4 apomucin is 930 kDa and it is comprised of a 850 kDa mucin-type subunit (MUC4α) and an 80 kDa membrane-tethered subunit (MUC4β) (Figure 2). Several allelic and splice-variants of MUC4 are also reported. MUC4a possesses three important domains [TR (tandem-repeat), NIDO (nidogen-like) and AMOP (adhesion-associated domain in MUC4 and other proteins)], while MUC4b has three EGF-like domains and a short cytoplasmic tail. The MUC4α-subunit is thought to participate in adhesion and anti-adhesion mechanisms, while a role of MUC4β in cell signaling is proposed. In our recent studies, using ‘loss' and ‘gain' of function approaches, we have shown a direct association of the MUC4 mucin with the metastatic PC phenotype and provided experimental evidence for a functional role of MUC4 in altered growth and invasive properties of tumor cells. MUC4 was significantly associated with motility/invasion and anti-adhesive properties of pancreatic tumor cells. Interestingly, our study also revealed a correlative decrease in HER2 expression upon downregulation of MUC4. We have observed that both MUC4 and HER2 co-localize with each other at the cell surface and in the cytoplasm of PC cells. The physical association between MUC4 and HER2 was confirmed by coimmunoprecipitation and in vivo co-clustering. Our subsequent studies have indicated that MUC4-mediated regulation of HER2 may occur by post-transcriptional mechanism(s). In other studies, we have observed that MUC4 expression in NIH3T3 mouse fibroblast cells leads to the oncogenic transformation of these cells. Taken together, the structural attributes of MUC4, its aberrant expression and functional role in the tumorigenicity and metastasis of cancer cells provide experimental evidence for the multifaceted roles of MUC4 in the progression cancer. Under normal conditions, MUC4 is localized at the apical surface of the epithelial cells. However, during the course of cancer progression, tumor cells lose polarity, allowing ubiquitous cell surface expression of MUC4 and its subsequent interaction with novel partner(s) such as HER2. Association of MUC4 with HER2 may protect disseminated tumor cell from anoikis via HER2-mediated mechanisms, thus facilitating the primary tumor growth. Overexpression of MUC4 on the cell surface further disrupts the interaction between adhesion molecules which may facilitate the motility and invasion properties of tumor cells. The process of metastasis may be further assisted by adhesion of MUC4 on endothelial cells by interacting with glycoproteins (Galectin-3 or selectins).
Currently, we are working on:
- Defining the mechanism(s) responsible for MUC4-mediated regulation of HER2 in pancreatic cancer cells.
- Determining the molecular mechanisms by which MUC4 contributes to tumor growth and metastasis.
- Investigating the co-operative action of MUC4 in combination with other defined oncogenic mutations, in the early development of pancreatic cancer.
In addition to these goals, MUC4 is being explored as a maker for early diagnosis and target for active and passive therapy in many cancers in our laboratory. In addition to MUC4, other projects are:
- Genetically engineered multivalent single chain antibody constructs for cancer therapy. This proposal is aimed to generate, characterize, increase production and affinity of multivalent antibody constructs reactive with the tumor associated Sialyl-Tn antigen present on TAG-72 and to determine the utility of these specific antibodies for the diagnosis and treatment of cancer. The phage display technology is being used for the development of new tumor-specific human monoclonal antibodies.
- Understanding the dysregulation of PD2/hPaf 1 and hPAF1 complex in cancers.
- Molecular and biochemical studies on PDF/MIC-1.
Chaturvedi P, Singh AP, and Batra SK. Structure, evolution, and biology of the MUC4 mucin. FASEB J. 22:966-981, 2008. Abstract
Chaturvedi P, Singh AP, Chakraborty S, Chauhan SC, Bafna S, Meza JL, Singh PK, Hollingsworth MA, Mehta PP, and Batra SK. MUC4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells. Cancer Res 68:2065-2070, 2008. Abstract
Davda JP, Jain M, Batra SK, Gwilt PR, and Robinson DH. A physiologically based pharmacokinetic (PBPK) model to characterize and predict the disposition of monoclonal antibody CC49 and its single chain fv constructs. Int Immunopharmacol 8:401-413, 2008. Abstract
Mimeault M and Batra SK. Recent progress on tissue-resident adult stem cell biology and their therapeutic implications. Stem Cell Rev 4(1):27-49, 2008. Abstract
Mimeault M and Batra SK. Targeting of cancer stem/progenitor cells plus stem cell-based therapies: the ultimate hope for treating and curing aggressive and recurrent cancers. Panminerva Med 50:3-18, 2008. Abstract
Mimeault M, Hauke R, and Batra SK. Recent advances on the molecular mechanisms involved in the drug resistance of cancer cells and novel targeting therapies. Clin. Pharmacol. Ther 83:673-691, 2008. Abstract
Mimeault M, Mehta PP, Hauke R, and Batra SK. Functions of normal and malignant prostatic stem/progenitor cells in tissue regeneration and cancer progression and novel targeting therapies. Endocr Rev 29:234-252, 2008. Abstract
Moniaux M, Chakraborty S, Yalniz M, Gonzalez J, Shostrom VK, Standop J, Lele SM, Ouellette M, Pour PM, Sasson AR, Brand RE, Hollingsworth MA, Jain M, and Batra SK. Early diagnosis of pancreatic cancer: Neutrophil gelatinase-associated lopocalin as a marker of pancreatic intraepithelial neoplasia. Br. J. Cancer 98:1540-1547, 2008. Abstract
Singh AP, Bafna S, Chaudhary K, Venkatraman G, Smith L, Eudy JD, Johansson SL, Lin MF, and Batra SK. Genome-wide expression profiling reveals transcriptomic variation and perturbed gene networks in androgen-dependent and androgen-independent prostate cancer cells. Cancer Letters 259:28-38, 2008. Abstract
Wittel UA, Hopt UT, and Batra SK. Cigarette smoke-induced pancreatic damage-experimental data. Langenbecks Arch Surg 393(4):581-8, 2008. Abstract
Witte UA, Wiech T, Chakraborty S, Boss B, Lauch R, Batra SK, and Hopt UT. Taurocholate-induced pancreatitis: A model of severe necrotizing pancreatitis in mice. Pancreas 36:e9-21, 2008. Abstract
Ponnusamy MP, Singh AP, Jain M, Chakraborty S, Moniaux N, and Batra SK. MUC4 activates HER2 signalling and enhances the motility of human ovarian cancer cells. Br. J. Cancer 99(3):520-6, 2008. Abstract
Senapati S, Chaturvedi P, Sharma P, Venkatraman G, Meza JL, El-Rifai W, Roy HK, and Batra SK. Deregulation of MUC4 in gastric adenocarcinoma: Potential pathobiological implication in poorly differentiated non-signet ring cell type gastric cancer. Br. J. Cancer 99(6):949-956, 2008. Abstract
Mimeault M, Batra SK. Recent progress on normal and malignant pancreatic stem/progenitor cell research: Therapeutic implications for the treatment of type 1 or 2 diabetes mellitus and aggressive pancreatic cancer. Gut. 57:1456-1468, 2008. Abstract
Ponnusamy MP, Batra SK. Ovarian cancer: Emerging concept on cancer stem cells. J Ovarian Res. 1(4):1-8, 2008. Abstract
Senapati S, Sharma P, Bafna S, Roy HK, Batra SK. The MUC gene family: Their role in the diagnosis and prognosis of gastric cancer. Histol Histopathol. 23:1541-1552, 2008. Abstract
Singh AP, Senapati S, Ponnusamy MP, Jain M, Lele SM, Davis JS, Remmenga S, Batra SK. Clinical potential of mucins in diagnosis, prognosis, and therapy of ovarian cancer. Lancet Oncol. 9(11):1076-85, 2008. Abstract
Bafna S, Singh AP, Moniaux N, Eudy JD, Meza JL, Batra SK. MUC4, a multifunctional transmembrane glycoprotein, induces oncogenic transformation of NIH3T3 mouse fibroblast cells. Cancer Res. 68:9231-9238, 2008. Abstract
Mimeault M, Batra SK. Recent insights into the molecular mechanisms involved in aging and the malignant transformation of adult stem/progenitor cells and their therapeutic implications. Aging Res Rev. 8:94-112, 2009. Abstract
Zhang L, Davis JS, Zelivianski S, Lin FF, Schutte R, Davis TL, Hauke R, Batra SK, Lin MF. Suppression of ErbB-2 in androgen-independent human prostate cancer cells enhances cytotoxic effect by gemcitabine in an androgen-reduced environment. Cancer Letter. 2009 May 23. [Epub ahead of print] Abstract
Munro EG, Jain M, Oliva E, Kamal N, Lele SM, Lynch MP, Guo L, Fu K, Sharma P, Remmenga S, Growdon WB, Davis JS, Rueda BR, Batra SK. Upregulation of MUC4 in cervical squamous cell carcinoma: pathologic significance. Int J Gynecol Pathol. 28(2):127-33, 2009. Abstract
Chipitsyna G, Gong Q, Anandanadesan R, Alnajar A, Batra SK, Wittel UA, Cullen DM, Akhter MP, Denhardt DT, Yeo CJ, Arafat HA. Induction of osteopontin expression by nicotine and cigarette smoke in the pancreas and pancreatic ductal adenocarcinoma cells. Int J Cancer. 125(2)276-285, 2009. Abstract
Mimeault M and Batra SK. Aging of tissue-resident adult stem/progenitor cells and their pathological consequences. Panminerva Med. 51:57-79, 2009.
Mimeault M and Batra SK. New methods for the characterization of tumorigenic and migrating cancer stem/progenitor cells. Methods in Molecular Biology. 568:139-49, 2009.
Bafna S, Kaur S, Momi N, and Batra SK. Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin. Br J Cancer. 101:1155-1161, 2009.
Moniaux N, Nemos C, Deb S, Zhu B, Dornreiter I, Hollingsworth MA, Batra SK. The human RNA polymerase II-associated factor 1 (hPaf1): a new regulator of cell-cycle progression. PLoS One. 4:e7077, 2009.
Ponnusamy MP, Deb S, Dey P, Chakraborty S, Rachagani S, Senapati, S, Batra SK. 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.
Rachagani S, Torres MP, Moniaux N, Batra SK. Current status of mucins in the diagnosis and therapy of cancer. Biofactors. 35:509-527, 2009.
Torres MP, Ponnusamy MP, Lakshmanan I, Batra SK. Immunopathogenesis of ovarian cancer. Minerva Med. 100:385-400, 2009.
Senapati S, Rachagani S, Chaudhary K, Johansson SL, Singh RK, Batra SK. Overexpression of macrophate inhibitory cytokine-1 (MIC-1) induces metastasis of human prostate cancer cells via FAK-RhoA signaling pathway. Oncogene. 29(9):1293-302, 2010.
Mimeault M, Johansson SL, Henichart JP, Depreux P, Batra SK. Cytotoxic effects induced by docetaxel, gefitinib and cyclopamine on side population and non-side population cell fractions from human invasice prostate cancer cells. Molecular Cancer Therapeutics. 9:617-630, 2010.
Mimeault M and Batra SK. Novel therapies against aggressive and recurrent epithelial cancers by molecular targeting cancer-and metastasis-initiating cells and their progenies. Anti-Cancer Agents Med Chem. 10(2):137-51, 2010.
Mimeault M and Batra SK. Recent advancements on the identification of immature cancer cells with the stem cell-like properties in different aggressive and recurrrent cancer types. Anticancer Agents Med Chem. 10:103, 2010.
Rachagani S, Kumar S, Batra SK. MicroRNA in pancreatic cancer: pathological, diagnostic and therapeutic implications. Cancer Lett. 292(1):8-16, 2010.
Mimeault M and Batra SK. Recent advances on skin-resident stem/progenitor cell functions in skin regeneration, aging and cancers and novel anti-aging and cancer therapies. J Cell Mol Med. 14(1-2)116-34, 2010.
Senapati S, Das S and Batra SK. Mucin-interacting proteins: from function to therapeutics. Trends in Biochemical Science. 35(4):236-45, 2010.
Mimeault M and Batra SK. New promi using drug targets in cancer- and metastasis-initiating cells and therapies. Drug Discovery Today. 15:354-45, 2010.
Luu Y, Junker W, Rachagani S, Das S, Batra SK, Heinrikson RL, Shekel LL and Ho SB. Human intestinal MUC17 mucin augments intestinal cell restitution and enhances healing of experimental colitis. International Journal of Biochemistry and Cell Biology. 42(6):996-1006, 2010.
Torres MP, Ponnusamy MP, Chakraborty S, Arafat HA, Das S, Batra SK. 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.
Higashi M, Goto M, Saitou M, Shimizu T, Rousseau K, Batra SK, Yonezawa S. Immunohistochemical study of mucin expression in perampullary adenomyoma. Hepatobiliary Pancreat. Surg. 17(3):275-83, 2010.
Bafna S, Kaur S, Batra SK. Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells. Oncogene. 29:2893-2904, 2010.
Ho SB, Luu Y, Shekels LL, Batra SK, Kandarian B, Evans DB, Zaworski PG, Wolfe CL, Heinrikson RL. Activity of recombinant cysteine-rich domain prpoteins derived from the membrane-bound MUC17/MUC3 family mucins. BBA. 1800(7):629-38, 2010.
Mimeault M and Batra SK. New advances on critical implications of tumor-and metastasis-initiating cells in cancer progression, treatment resistance and disease recurrence. Histology and Histopathology (Cellular and Molecular Biology). 25:1057-1073, 2010.
Mimeault M, Johansson SL, Senapati S, Momi N, Chakraborty S, Batra SK. MUC4 down-regulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies. Cancer Letters. 295:69-84, 2010.
Mimealt M and Batra SK. Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer progression. J Cell Physiol. 224(3):626-635, 2010.
Chakraborty S, Swanson BJ, Bonthu N, Batra SK. Immunohistochemical analysis of MUC4 mucin expression in cutaneous pathologies. J Clinical Pathology. 63:579-584, 2010.
Togami S, Nomoto M, Higashi N, Goto M, Yonezawa S, Tsuji T, Batra SK, Douchi T. Expression of mucin antigens (MUC1 and MUC16) as a propgnostic factor for mucinous adenocarcinoma of the uterine cervix. Journal of Obstetrics and Gynaecology Research. 36(3):588-97, 2010.
Current Grants and Contracts:
R01 CA138791-01 (NIH)
Novel deregulated genes in the etiology and progression of human prostate cancer
5/1/10 - 2/28/15
R01 CA131944 (NIH)
Molecular markers for the diagnosis of pancreatic cancer
7/2/08 - 3/31/13
R01 CA133774 (NIH)
Smoking and pancreatic cancer
3/1/08 - 12/31/12
2R01 CA78950-12 (NIH)
Molecular studies on MUC4 mucin gene
9/1/08 - 6/30/12
Surinder K. Batra
William G. Chaney
G. Stanley Cox
Richard G. MacDonald
Parmender P. Mehta
Robert F. Ramaley