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
Phone: 402-559-5455 (Office)
Ph.D., Kurukshetra University (NDRI), INDIA, 1983
Post-doctoral Fellow, North Carolina State University, Raleigh, NC, USA, 1983-1986
Post-doctoral Fellow, Duke University Medical Center, Durham, USA, 1988-1991
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.
Total 362 Publications (selected shown below from last three years):
Costa-Silva B, Aiello NM, Singh S, Zhang H, Thakur BK, Becker A, Hoshino A, Mark MT, Molina H, Xiang J, Zhang T, Theilen T-M, García-Santos G, Williams , Ararso Y, Huang Y, Rodrigues G, Shen T-L, Labori KJ, Lothe IMB, Kure EH,. Ocean AJ, Hernandez J, Doussot A, Ebbesen S, Grandgenett P, Hollingsworth MA, Jain M, Mallya K, Batra SK,. Jarnagin WR, Schwartz RE, Matei I, Peinado H, Stanger B, Bromberg J, and Lyden DV (2015). Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nature Cell Biology 2015 Jun;17(6):816-26. doi: 10.1038/ncb3169. Epub 2015 May 18. PMID: 25985394
Chari ST, Kelly K, Hollingsworth MA, Thayer SP, Ahlquist DA, Andersen DK, Batra SK, Brentnall TA, Canto M, Cleeter D, Firpo MA, Gambhir SS, Go VL, Hines OJ, Kenner BJ, Klimstra DS, Lerch MM, Levy MJ, Maitra A, Mulvihill SJ, Petersen GM, Rhim AD, Simeone DM, Srivastava S, Tanaka M, Vinik AI, Wong D. Early Detection of Sporadic Pancreatic Cancer: Summative Review. Pancreas, 2015 Apr 23. [Epub ahead of print], 2015. PMID: 25931254
Higashi, M, Yokoyama, S, Yamamoto, T, Goto Y, Hiraki T, Hashimoto S, Fukukura Y, Koriyama C, Shinchi H, Jain M, Batra S.K., and Yonezawa S. Mucin expression in EUS-FNA specimens is a useful prognostic factor in pancreatic ductal adenocarcinoma. Pancreas, in press, on line, 2015 Apr 2. PMID 25906442
Joshi S, Kumar S, Bafna S, Rachagani S, Wagner KU, Jain M, and Batra SK. Genetically engineered mucin mouse models for inflammation and cancer. Cancer Metastasis Review, 41(3):277-88, 2015, PMID 25634251
Kumar S, Torres M, Kaur S, Rachagani S, Momi N, Baine M, Joshi S, Gilling C, Wyatt T, Jain, M, Joshi S and Batra SK. Smoking accelerates pancreatic cancer progression by promoting differentiation of MDSCs and inducing HB-EGF expression in macrophages. Oncogene 34(16):2052-60, 2015. PMID24909166
Kamikawa Y, Kanmura Y, Hamada T, Yamada N, Macha MA, Batra SK, Higashi M, Yonezawa S, Sugihara K. Co-expression of MUC1 and MUC4 is associated with poor prognosis in oral squamous cell carcinoma patients. Int. J of Clinical Oncol, 20(2): 298-307, 2015. PMID: 24909613.
Yan, Y, Hein, A., Greer, P.M., Batra, S.K., Wang, Z., Kolb, R.H. & Cowan, K.H. A novel function of HER2/Neu in the activation of G2/M checkpoint in response to g-irradiation. Oncogene, 34(17):2215-26, 2015, PMID 24909175
Jain S, Sukhlabaidya S, Das B, Raghav SK, Batra SK, and Senapati, S. TLR4LR activation by lipopolysaccharide confers survival advantage to growth factor deprived prostate cancer cells. Prostate, 75(10):1020-33 2015, PMID 25833062
Kumar V, Mondal G, Slavik P, Rachagani S, Batra SK, and Mahato RI. Co-delivery of Small Molecule Hedgehog Inhibitor and miRNA for treating Pancreatic Cancer. Molecular Pharmaceutics, 12(4):1289-98, 2015, PMID 25679326
Das S, Rachagani S, Torres-Gonzalez MP, Lakshmanan I, Majhi PD, Smith LM, Wagner KU, Batra SK. Carboxyl-terminal domain of MUC16 imparts tumorigenic and metastatic functions through nuclear translocation of JAK2 to pancreatic cancer cells. Oncotarget, 6(8):5772-5787, 2015, PMID 25691062
Macha MA, Krishn SR, Jahan R, Banerjee K, Batra SK, Jain M. Emerging potential of natural products for targeting mucins for therapy against inflammation and cancer. Cancer Treat Rev. 41(3):277-288, 2015, PMID 25624117
Seshacharyulu P, Ponnusamy MP, Rachagani S, Lakshmanan I, Haridas D, Yan Y, Ganti AK and Batra SK. Targeting EGF-receptor(s)–STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer. Oncotarget, 6(7):5164-81, PMID 25686822
Macha M, Rachagani S, Pai P, Gupta S, Lydiatt W, Smith R, Johansson S, Lele S, Kakar S, Lee J, Meza J, GantiA, JainM and Batra SK. MUC4 Regulates Cellular Senescence in Head and Neck Squamous Cell Carcinoma (HNSCC) through p16/Rb Pathway. Oncogene, 34(13):1698-708, 2015, PMID 24747969
Mimeault M, Rachagani S, Muniyan S, Seshacharyulu P, Johansson SL, Datta K, Lin MF and Batra SK. Inhibition of Hedgehog Signaling Improves the Anti-carcinogenic Effects of Docetaxel in Prostate Cancer. Oncotarget, 6(6):3887-903, 2015, PMID 25682877
Pandey P, Rachagani S, Das S, Seshacharyulu P, Sheinin Y, Naslavsky N, Pan Z, Smith BL, Peters HL, Radhakrishnan P, McKenna NR, Giridharan SS, Haridas D, Kaur S, Hollingsworth MA, MacDonald RG, Meza JL, Caplan S, Batra SK, Solheim JC. Amyloid precursor-like protein 2 (APLP2) affects the actin cytoskeleton and increases pancreatic cancer growth and metastasis. Oncotarget, 10;6(4):2064-75, 2015, PMID 25576918
Lakshmanan I, Ponnusamy MP, Macha MA, Haridas D, Majhi PD, Jain M, Batra SK and Ganti AK. Mucins in lung Cancer: Diagnostic, Prognostic and Therapeutic Implications. Journal of Thoracic Oncology, 10(1):19-27, 2015, PMID 25319180
Das S, and Batra SK. Pancreatic Cancer Metastasis: Are we being Pre-EMTed? Curr Pharm Des., 21(10):1249-55, 2015, PMID 25506899
Rachagani S, Macha MA, Heimann N, Seshacharyulu P, Haridas D, Chugh S, Batra SK. Clinical implications of miRNAs in the pathogenesis, diagnosis and therapy of pancreatic cancer. Adv Drug Deliv Rev., 81C:16-33, 2015, PMID 25453266.
Krasnoslobodtsev AV, Torres MP, Kaur S, Vlassiouk IV, Lipert RJ, Jain M, Batra SK*, and Lyubchenko YL*. Nano-immunoassay with improved performance for detection of cancer biomarkers. Nanomedicine. 11(1):167-73.2015. *Both are equal corresponding authors. PMID 25200613
Kumar S, Das S, Rachagani S, Kaur S, Joshi S, Johansson SL, Ponnusamy MP, Jain M, Batra SK. NCOA3-mediated upregulation of mucin expression via transcriptional and post-translational changes during the development of pancreatic cancer. Oncogene, 2014 Dec 22, doi:10.1038/onc.2014.409. PMID 25531332
Yan, Y, Hein, A.L, Etekpo A, Burchett K.M, Lin C, Enke C.A, Batra, S.K, Cowan, K.H, and Ouellette M.M Inhibition of RAC1 GTPase sensitizes pancreatic cancer cells to γ-irradiation. Oncotarget, 5(21):10251-70, 2014, PMID 25344910
Chakraborty S, Smith L, Ganti AK, Bonthu N, Batra SK. Author's response to "Country of origin and breast cancer survival". Asia Pac J Clin Oncol, 111(6):1139-49, 2014, PMID 24965198
Shibahara H, Higashi M, Yokoyama S, Rousseau K, Kitazono I, Osako M, Shirahama H, Tashiro Y, Kurumiya Y, Narita M, Kuze S, Hasagawa H, Kato T, Kubota H, Suzuki H, Arai T, Sakai Y, Yuasa N, Fujino M, Kondo S, Okamoto Y, Yamamoto T, Hiromatsu T, Sasaki E, Shirai K, Kawai S, Hattori K, Tsuji H, Okochi O, Sakamoto M, Kondo A, Konishi N, Batra SK, Yonezawa S. A Comprehensive Expression Analysis of Mucins in Appendiceal Carcinoma in a Multicenter Study: MUC3 Is a Novel Prognostic Factor. PLos One; 31; 9(12):e115613, 2014, PMID 25551773
Ponnusamy MP, Batra SK. Insights into the role of nicotine in pancreatic stem cell activation and acinar dedifferentiation. Gastroenterology, 147(5):962-5, 2014, PMID25265575
Joshi S, Kumar S, Choudhury, A, Poonusamy MP and Batra S.K. Altered Mucins (MUC) Trafficking in Benign and Malignant Conditions. Oncotarget, 5(17):7272-84, 2014, PMID25261375
Niv Y, Boltin D, Halpern M, Cohen M, Levi Z, Vilkin A, Morgenstern S, Manugian V, St Lawrence E, Gagneux P, Kaur S, Sharma P, Batra SK, Ho SB. Membrane-bound mucins and mucin terminal glycans expression in idiopathic or Helicobacter pylori, NSAID associated peptic ulcers. World J Gastroenterol, 20(40):14913-20, 2014, PMID25356051
Kakar S.S, Ratajczak M.Z, Powell K.S, Moghadamfalahi M, Miller D.M, Batra S.K., and Singh S.K. Withaferin A alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting tumor stem cells. PLoSOne, 9(9):e107596, 2014, PMID25264898
Souchek J.J., Baine, M.J., Lin C, Kaur, S., Rachagani S., Gupta, S., Lester K., Zheng, D., Chen S., Smith L., Lazenby A., Johansson S.L., Jain M., and Batra SK. Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitization. British Journal of Cancer, 111(6):1139-49, 2014. PMID25025965
Haridas D, Ponnusamy MP, Chugh S, Lakshmanan I, Seshacharyulu P, and Batra SK. MUC16: molecular analysis and its functional implications in benign and malignant condition. FASEB, 28(10):4183-99, 2014, PMID25002120
Mimeault M and Batra SK. Introduction at the special issue on implications of cancer stem/progenitor cell concepts in molecular oncology and novel targeted therapies. Molecular Aspects of Medicine, 39:1-2, PMID24080440
Vaz A.P., Ponnusamy M.P, Rachagani S., Dey P., Ganti AK, and Batra. S.K. Novel role of pancreatic differentiation 2 in facilitating self-renewal and drug resistance of pancreatic cancer stem cells. British Journal of Cancer, 111(3):486-96, 2014, PMID 25003666/PMCID 4119968
Vaz A.P, Ponnusamy M.P, Seshacharyulu P, and Batra S.K. A concise review on the current understanding of pancreatic cancer stem cells. Journal of Cancer Stem Cell Research, 2:e1004, 2014
Muniyan S, Ingersoll MA, Batra SK, and Lin MF. Cellular prostatic acid phosphatase, a PTEN-functional homologue in prostate epithelia, functions as a prostate-specific tumor suppressor. BBA Reviews in Cancer, 1846, 88-98, 2014, PMID 24747769/PMC 4140952
Dey P, Rachagani S, Vaz A, Ponnusamy PM and Batra SK. Paf1/PD2 depletion in pancreatic acinar cells promotes acinar-to-ductal metaplasia. Oncotargets, 5(12): 4480-91. 2014, PMID 24947474 /PMC4147339
Gupta S, Batra S and Jain M. Antibody labeling with radioiodine and radiometals. Methods Mol Biol. 1141:147-57, 2014, PMID 24567137/PMC4095879
Macha M.A, Seshacharyulu P., Krishn S.R, Pai P., Rachagani S, Jain M, and Batra SK MicroRNAs (miRNA) as Biomarker(s) for Prognosis and Diagnosis of Gastrointestinal (GI) Cancers. Current Pharmaceutical Designs, 1381-6128, 2014. PMID24479799/PMC411360
Mimeault M and Batra SK. Altered gene products involved in the malignant reprogramming of cancer stem/progenitor cells and multitargeted therapies. Molecular Aspects of Medicine, 39:3-32, 2014. PMID 3994756/PMC3938987
Yokoyama S, Kitamoto S, Higashi M, Goto Y, Hara T, Ikebe D, Yamaguchi T, Arisaka Y, Niihara T, Nishimata H, Tanaka S, Takaori K, Batra SK and Yonezawa S. Diagnosis of pancreatic neoplasms using a novel method of DNA methylation analysis of mucin expression in pancreatic juice. PLoS One. 9(4):e93760, 2014. PMID2471462/PMC3979708
Shibahara H, Higashi M, Koriyama C, Yokoyama S, Kitazono I, Kurumiya Y, Narita M, Kuze S, Kyokane T, Mita S, Arai T, Kato T, Yuasa N, Yamaguchi R, Kubota H, Suzuki H, Baba S, Rousseau K, Batra SK, and Yonezawa S. Pathobiological Implications of Mucin (MUC) Expression in the Outcome of Small Bowel Cancer. PLoS One. 9(4):e86111, 2014. PMID24722639/PMC3982950
Kaur S, Momi N, Chakraborty S, Wagner DG, Horn AJ, Lele SM, Theodorescu D, Batra SK. Altered Expression of Transmembrane Mucins, MUC1 and MUC4, in Bladder Cancer: Pathological Implications in Diagnosis. PLoS One 9(3):e92742. 2014 PMID24671186/PMC3966814
Current Grants and Contracts:
NCI UO1 CA185148 01 (NIH) Principal Investigators: Surinder K. Batra
Title: MIC-1 and its functional partners in prostate cancer racial disparity
Dates and costs of entire project 5/01/15-4/30/20 $1,692,650
RO1 CA183459 (NIH)
Principal Investigator: Surinder K. Batra
Title: Targeting Mucin and EGFR Axis in Pancreatic Cancer
Dates and costs of entire project 9/01/14-8/31/19 $1,558,295
U54 CA163120 (NIH)
Principal Investigator: Surinder K. Batra
Title: Pancreatic Tumor Microenvironment Network
Dates and direct costs of entire project 9/26/011-7/31/16 $4, 16,161
RO1 CA138791 (NIH)
Principal Investigator: Surinder K. Batra
Title: Novel Deregulated Genes in the Etiology and Progression of Human Prostate Cancer
Dates and costs of entire project 5/01/010-2/28/16 $1,846,610
NIH SPORE P50 CA127297
Project (#2) Leader: Surinder K. Batra
Title of Project: Novel target(s) in the radiosensitization of pancreatic cancer
Program Director: Michael Hollingsworth
Title of the Program: SPORE in gastrointestinal cancer
Dates and costs of entire project 9/01/14-8/31/19 $11,362,000
2U01 CA111294 MPI (NIH)
Principal Investigators: Michael Hollingsworth and Surinder K. Batra
Title: Early diagnosis of pancreatic cancer.
Dates and direct costs of entire project 9/13/10-6/30/15 $3,289,988