Professor and Chairman Department of Biochemistry and Molecular Biology, College of Medicine, Stokes-Shackelford Professor, Associate Director for Education and Training, Fred & Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer
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.
Kitazono I, Higashi M, Kitamoto S, Yokoyama S, Horinouchi M, Osako M, Shimizu T, Tabata M, Batra S.K, Goto M and Yonezawa S. Expression of MUC4 mucin is observed mainly in the intestinal-type of intraductal papillary mucinous neoplasm of the pancreas. Pancreas, Oct;42(7):1120-8, 2013
Radhakrishnan P, Mohr AM, Grandgenett, PM, Batra SK, and Hollingsworth MA. MicroRNA-200c modulates the expression of MUC4 and MUC16 by directly targeting their coding sequences in human pancreatic cancer. PLoSOne, Dec 1;341(2):166-77, 2013
Macha MA, Rachagani S,Chakraborty S, Gupta S, Pai P, Ponnusamy MP, Batra SK, and Jain M. Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling. Cancer Letters,
Pai, P, Rachagani, S, Are C and Batra S.K. Prospects of miRNA-based therapy for pancreatic cancer. Current Drug Tragets, 14(10):1101-9, 2013.
Macha M, Batra .S.K, and Gant AK. Profile of vismodegib and its potentialin the treatment of advanced basal cell carcinoma. Cancer Management and Research, 5:197-203, 2013.
Shimizu T, Torres MP, Chakraborty S, Souchek JJ, Rachagani S, Kaur S, Macha M, Ganti AK, Hauke RJ, Batra SK. Holy Basil leaf-extract decreases tumorigenicity and metastasis of aggressive human pancreatic cancer cells in vitro and in vivo: Potential role in therapy. Cancer Letters, 336(2):270-80, 2013
Pandey P, Seshacharyulu P, DasS, RachaganiS, Ponnusamy MP, Yan Y, JohanssonSL, Datta K, LinMF and Batra SK. Impaired expression of protein phosphatase 2A subunits enhances metastatic potential of human prostate cancer cells through activation of AKT pathway. British J. Cancer, 108(12):2590-600, 2013.
Seshacharyulu P, Pandey P, Datta K, and Batra SK. Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Letters, 335(1):9-18 2013
Horn A, Chakraborty S, Dey P, Haridas D, Souchek J, Batra SK, and Lele SM. Immunocytochemistry for MUC4 and MUC16 is a useful adjunct in the diagnosis of pancreatic adenocarcinoma on fine-needle aspiration cytology. Arch Pathol Lab Med, 137(4):546-51, 2013
Momi N, Poonusamy, Kaur S, Rachagani S, MP, Kunigal, S.S, Chellappan Sand Batra SK Nicotine up-regulates MUC4 mucin via α7 nicotinic acetylcholine receptor and JAK2/STAT3 signaling cascade. Oncogene, 32(11):1384-95, 2013.
Mimeault M. and Batra SK Development of animal models underlining mechanistic connections between prostate inflammation and cancer: A persistent challenge and perspectives. World J Clin Oncol.4(1):4-13,2013.
Majhi PD, Lakshmanan I, Ponnusamy MP, Jain M, Das D, Kaur S, Shimizu ST, West WW, Johansson SL, Smith LM, Yu, . Rolle CE, Sharm P, Carey GB, Batra SK and Ganti AP. Pathobiological implications of MUC4 in non-small-cell lung cancer. Journal of Thoracic Oncology, 8(4):398-407, 2013
Lin WC, Rajbhandari N, Liu C, Sakamoto K, Zhang Q, Triplett AA, Batra SK, Opavsky R, Felsher DW, Dimaio DJ, Hollingsworth MA, Morris JP 4th, Hebrok M, Witkiewicz AK, Brody JR, Rui H, and Wagner KU. Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer. Cancer Research 73(6):1821-1830, 2013.
Kaur S, Baine MJ, Guha S, Ochi N, Chakraborty S, Mallya K, Thomas C, Crook J, Wallace MB, Woodward TA, Jain M, Singh S, Sasson AR, Skinner V, Raimondo M, and Batra SK. Neutrophil Gelatinase-Associated Lipocalin, Macrophage Inhibitory Cytokine 1, and Carbohydrate Antigen 19-9 in Pancreatic Juice: Pathobiologic Implications in Diagnosing Benign and Malignant Disease of the Pancreas.Pancreas,42(3):494-501, 2013.
Chakraborty S, Tarantolo S.R, Batra S.K and Hauke RJ. Second Primary Malignancies in Patients with Renal Cell Carcinoma- A SEER Based Study. American Journal of Clinical Oncology, 36(2): 132-142, 2013.
Mimeault M., Johansson S.L., Batra SK Marked improvement of anticarcinogenic effects induced by docetaxel on highly metastatic and androgen-independent prostate cancer cells by down-regulating macrophage inhibitory cytokine-1. British Journal of Cancer 108(5):1079-91, 2013.
Vaz, AP, Ponnusamy, MP and Batra SK Cancer stem cells and therapeutic targets: an emerging field for cancer treatment. Drug, Delivery, and Translational Research,3(2), 113-120, 2013.
Mukhopadhyay P, Lakshmanan I, Ponnusamy MP, Chakraborty S, Jain M, Pai P, Smith LM, Subodh LM, and Batra SK MUC4 overexpression augments cell migration and metastasis through EGFR family proteins in triple negative breast cancer cells. PLoSOne, 8(2):e54455 2013.
Mimeault, Mand Batra SK Emergence of Zebrafish models in oncology for validating novel anticancer drug targets and nanomaterials. Drug Discovery Today 18(3-4):128-40, 2013.
Gnanapragassam, V.S, Jain M and Batra SK Analysis of Tumor Associated Mucin Glycotopes by Western Transfer Methods. Pancreatic Cancer: Methods and Protocols (Methods in Molecular Biology), 980:331-40, 2013.
Kaur S,Baine MJ, Chakraborty S, , Mallya K, Smith LM.,Sasson A, Brand R, Guha S, Jain M, Wittel U, and Batra SK. Comparison of plasma NGAL, MIC-1 and CA19-9 as biomarkers in the diagnosis of pancreatic ductal adenocarcinoma. PLoSOne; 8(2):e55171,2013.
Baine M, Mallya K and Batra SK Quantitative Real-Time PCR Expression Analysis of Peripheral Blood Mononuclear Cells in Pancreatic Cancer Patients. Pancreatic Cancer: Methods and Protocols (Methods in Molecular Biology), 980:157-73, 2013
Mimeault M and Batra SK Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. Journal of Cellular and Molecular Medicine,17(1):30-54, 2013.
Momi N, Kaur S, Krishan SR and Batra SK. Discovering the route from inflammation to pancreatic cancer. Minerva Gastroenterology Dietol 58:283-97, 2012
Rachagani S, Torres MP, Kumar S, Haridas D, Baine M, Macha MA, Kaur S, Ponnusamy MP, Dey P, Seshacharyulu P, Johansson SL, Jain M, Wagner KU, and Batra SK. Mucin (Muc) expression during pancreatic cancer progression in spontaneous mouse model: potential implications for diagnosis and therapy. J. Hematol Oncol. 5:68, 2012.
Hamada, T, Nomura, M., Kamikawa, Y, Yamada, N, Batra S.K, Yonezawa, S, and Sugihara K. Aberrant Expression of MUC1 Mucin is Associated with Tumor Aggressiveness, Subsequent Lymph Node Metastasis and Poor Prognosis in Oral Squamous Cell Carcinoma. Cancer 118(21):5251-64, 2012.
Dey P, Rachagani S, Chakraborty S, Singh PK, Zhao X, Gurumurthy CB, Anderson JM, Lele S, Hollingsworth MA, Band V and Batra SK Overexpression of Ecdysoneless (Ecd) in Pancreatic Cancer and its Role in Oncogenesis by Regulating Glycolysis. Clinical Cancer Research, 18(22):6188-98, 2012.
TamuraY, HigashiM, KitamotoS, YokoyamaS, OsakoM,HorinouchM, ShimizuT, TabataM, Batra S.K, Goto M and Yonezawa S. MUC4 and MUC1 Expression in Adenocarcinoma of the Stomach Correlates with Vessel Invasion and Lymph Node Metastasis: An Immunohistochemical Study of Early Gastric Cancer. PLosOne, 7(11):e49251, 2012.
Kaur S, Baine MJ, Jain M, Sasson AR, and BatraSK. Early diagnosis of pancreatic cancer: Challenges and New Developments. Clinical Biomarkers, 6(5):597-612, 2012.
RachaganiS, Macha MA, Ponnusamy MP, Haridas D, Kaur S, Jain M, and Batra SK MUC4 potentiates invasive and metastatic behavior of pancreatic cancer cells through stabilization of fibroblast growth factor receptor 1 (FGFR1). Carcinogenesis,33(10):1953-64,2012.
Kitamoto S, Yokoyama S, Higashi M, Yamada N, Shyuichiro M, Takao S,Batra S.K and Yonezawa S Upregulation of MUC17 by HIF1alpha-mediated Hypoxic Response and Requires a Methylaiton-free Hypoxia Responsible Element in Human Pancreatic Cancer. PLoS One, 7(9):e44108, 2012.
Momi N, Kaur S., Poonusamy, Kumar S, Wittel UAand Batra SK Interplay Between Smoking-induced Genotoxicity and Altered Signaling in Pancreatic Carcinogenesis. Carcinogenesis33(9):1617-28, 2012.
Hamada T, Wakamatsu T Miyahara M, Nagata S, Nomura M, Kamikawa Y, Yamada N, Batra SK., Yonezawa S, and Sugihara, K. MUC4: a novel prognostic factor of oral squamous cell carcinoma International J. Cancer, 130(8):1768-76, 2012.
Senapati, S, Gnanapragassam VS, Moniaux N, Momi N, and Batra SK. Role of MUC4-NIDO domain in the MUC4-mediated metastasis of pancreatic cancer cells. Oncogene, 31(28):3346-56, 2012.
Chen AC, Migliaccio I, Rimawi M, Lopez-Tarruella S, Creighton CJ, Massarweh S, Huang C, Wang YC, Batra SK, Gutierrez MC, Osborne CK, Schiff R.. Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies. Breast Cancer Research Treatment, 134(2):583-93, 2012
Sadanandam, A, Sidhu, SS, Wullschleger S, Singh S, Varney, ML., Yang, CS, Ashor A, Batra S.K and Singh R.K. Secreted Semaphorin 5A mediates Reduced Pancreatic Tumor Burden but Enhanced Micrometastasis and Endothelial Cell Proliferation. British J. Cancer, 107(3):501-7, 2012.
Torres MP, Rachagani S, Purohit V, Pandey P, Joshi S, Moore ED, Johansson SL, Singh PK, Ganti AK, and Batra SK. Graviola: A novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism. Cancer Letters 323(1):29-40, 2012
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.
Mimeault M, Johansson SL, and Batra SK Pathobiological Implications of the Expression of EGFR, pAkt, NF-kappaB and MIC-1 in Prostate cancer Stem Cells and their Progenies PLoS One, 7(2):e31919, 2012.
Tarang S, Kumar S and Batra SK Mucins and Toll-Like Receptors: Kith and Kin in infection and cancer. Cancer Letters 321(2):110-9, 2012.
Chakraboty S., Kaur S, Guha S., and Batra SK Multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and Cancer. BBA Reviews in Cancer, 1826(1):129-169, 2012.
Kelsey L, Katoch P, Johnson, K.E, Batra S.K, and Mehta PP. Retinoids regulate the formation and degradation of GAP junctions in androgen-responsive human prostate cancer cells. PLoS One, 7(4):e32846, 2012.
Mimeault M., and Batra SK Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. World Journal of Clinical Oncology,3(3):32-42,2012.
Torres M.P, Chakraborty S, Souchek J, and Batra SK. Mucin-based Targeted Pancreatic Cancer Therapy. Current Pharmaceutical Design,18(17):2472-81,2012.
Lakshmanan I, Ponnusamy M.P, Das S, Chakraborty S, Haridas D., Mukhopadhyay P, Lele S.M and Batra SK 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.
Higashi M, Yamada N, Yokoyama S, Kitamoto S, Tabata K, Koriyama C, Batra SK, and Yonezawa S. Pathobiological implications of MUC16/CA125 expression in intrahepatic Cholangiocarcinoma-Mass Forming Type. Pathobiology, 79(2):101-106, 2012
Seshacharyulu,P, Ponnusamy, MP, Haridas, D, Jain, M, Ganti A.K and Batra SK Targeting the EGFR signaling pathway in cancer therapy. Expert Opinions on Therapeutic Targets, 16, 15-31, 2012.
Kaur S, Venktaraman G, Jain M, Senapati S, Garg P.K and Batra SK Recent advances in antibody-based imaging for solid tumor. Cancer Letters 315, 97-111, 2012.
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