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Surinder K. Batra
Ph.D., NDRI (Kurukshetra Univ.), India, 1983
Chairman and Professor, Biochemistry and Molecular Biology
Distinguished Helen Freytag Professor of Cancer Biology
Senior Associate Dean for Research and Development
College of Medicine, Eppley Cancer Institute
DRC I, Room 7052, University of Nebraska Medical Center
985870 Nebraska Medical Center
Omaha, NE 68198-5870
Phone: (402) 559-5455 (Office)
(402) 559-7754 (Lab)
Fax: (402)559-6650
Email:sbatra@unmc.edu
Click here for biographical sketch and further publications.
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:
I: Defining the mechanism(s) responsible for MUC4-mediated regulation of HER2 in pancreatic cancer cells.
II: Determining the molecular mechanisms by which MUC4 contributes to tumor growth and metastasis.
III: 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.
RECENT PUBLICATIONS:
Mimeault M and Batra SK. Recent advances on multiple tumorigenic cascades involved in prostatic cancer progression and targeting therapies. Carcinogenesis 27:1-22, 2006. Abstract
Wittel WA, Andrianifahanana M, Pandey KK, Johansson SL, Cullen DM, Akhter MP, Brand RE, Prokopczyk B, and Batra SK. Chronic pancreatic inflammation induced by environmental tobacco smoke inhalation in rats. American Journal of Gastroenterology 101:148-159, 2006. Abstract
Singh AP, Chauhan SC, Bafna S, Johansson SL, Jain M, Smith LM, Moniaux N, Lin MF, and Batra SK Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas. Prostate 66:421-429, 2006. Abstract
Mimeault M, Moore E, Moniaux N, Hénichart JP, Depreux P, Lin MF, and Batra SK. Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. International Journal of Cancer 118(4):1022-31, 2006. Abstract
Yuan TC, Veeramani S, Lin FF, Kondrikou D, Zelivianski S, Igawa T, Karan D, Batra SK, and Lin MF. Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. Endocrine-Related Cancer 13:151-167, 2006. Abstract
Moniaux N, Nemos C, Schmied B Chauhan S, Deb S, Morikane K, Choudhury A, Vanlith M, Sutherlin M, Sikela JM, Hollingsworth MA, and Batra SK. The human homologue of the RNA polymerase II-associated factor 1 (hPaf1), localized on the 19q13 amplicon, is associated with tumorigenesis. Oncogene 25:3247-57, 2006. Abstract
Andrianifahanana M, Moniaux N, and Batra SK. Regulation of mucin expression: Mechnistic aspects and implications for cancer and inflammatory diseases. Biochimic Biophysica Acta 1765 (2):189-222, 2006. Abstract
*Moniaux N, *Junker WM, Singh AP, Jones AM, and Batra SK. Characterization of human mucin MUC17: Complete coding sequence and organization. J Biol Chem 281:23676-85, 2006. (* both these authors have equal contribution) Abstract
Tamada S, Shibahara H, Higashi M, Goto M, Batra, SK, Imai K, and Yonezawa S. MUC4 is a Novel Prognostic Factor of Extra-hepatic Bile Duct Carcinoma. Clinical Cancer Research 12(14):4257-64 2006. Abstract
Mitra S, Annamalai L, Chakraborty S, Johnson K, Song XH, Batra SK, and Mehta PP. Androgen-regulated formation and degradation of gap junctions in androgen-responsive human prostate cancer cells. Molecular Biology Cell 17:5400-5416, 2006. Abstract
Andrianifahanana M, Chauhan SC, Choudhury A, Moniaux N, Brand RE, Sasson AA, Pour PM, and Batra SK. MUC4-expressing pancreatic adenocarcinomas show elevated levels of both T1 and T2 cytokines: potential pathobiologic implications. American Journal Gastroenterology 101:2319-2329, 2006. Abstract
Jhala N, Jhala D, Vickers SM, Eltoum I, Batra SK, Manne U, Eloubeidi M, Jones JJ, and Grizzle WE. Biomarkers in Diagnosis of pancreatic carcinoma in fine-needle aspirates, American Journal of Clinical Pathology 126:572-579, 2006. Abstract
Ringel J, Jesnowski R, Moniaux N, Luttges J, Ringel J, Choudhury A, Batra SK, Kloppel G, and Lohr M. Aberrant expression of a disintegrin and metalloproteinase 17/tumor necrosis factor-alpha converting enzyme increases the malignant potential in human pancreatic ductal adenocarcinoma. Cancer Research 66:9045-9053, 2006. Abstract
Chauhan SC, Singh AP, Ruiz F, Johansson SL, Jain M, Smith LM, Moniaux N, and Batra SK. Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125). Modern Pathology 19:1386-1394, 2006. Abstract
Mimeault M and Batra SK. Concise review: recent advances on the significance of stem cells in tissue regeneration and cancer therapies. Stem Cells 24:2319-2345, 2006. Abstract
Wittel UA, Singh AP, Henley BJ, Andrianifahanana M, Akhter MP, Cullen DM, and Batra SK. Cigarette smoke-induced differential expression of the genes involved in exocrine function of the rat pancreas. Pancreas 33:364-370, 2006. Abstract
De Clerck YA, Weissman BE, Yu D, Parsons R, Bar-Eli M, Roy-Burman P, Seewaldt VL, Cress AE, Languino LR, Batra SK, Tang CK, Sheng S, Chen WT, Chellappan S, Cheng SY, Ladisch S, McCarthy JB, Coussens LM, and Cohen MB. Tumor Progression and Metastasis from Genetic to Microenvironmental Determinants: A Workshop of the Tumor Progression and Metastasis NIH Study Section in Honor of Dr. Martin L. Padarathsingh, May 31, 2006, Georgetown, Washington, DC. Cancer Biology and Therapy 5:1588-1599, 2006. Abstract
Singh AP, Chauhan SC, Andrianifahanana M, Moniaux N, Meza JL, Copin MC, Van S, Hollingsworth MA, Aubert JP, and Batra SK. MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms. Oncogene 26:30-41, 2007. Abstract
Chen SJ, Karan D, Johansson SL, Lin FF, Zeckser J, Singh AP, Batra SK, and Lin MF. Prostate-derived factor as a paracrine and autocrine factor for the proliferation of androgen receptor-positive human prostate cancer cells. Prostate 67:557-571, 2007. Abstract
Tsutsumida H, Goto M, Kitajima S, Kubota I, Hirotsu Y, Wakimoto J, Batra SK, Imai K, and Yonezawa S. MUC4 expression correlates with poor prognosis in small-sized lung adenocarcinoma. Lung Cancer 55:195-203, 2007. Abstract
Singh AP, Chaturvedi P, and Batra SK. Emerging roles of MUC4 in cancer: a novel target for diagnosis and therapy. Cancer Research 67:433-436, 2007. Abstract
Mimeault M, Venkatraman G, Johansson SL, Moore E, Henichart JP, Depreux P, Lin MF, and Batra SK. Novel combination therapy against metastatic and androgen-independent prostate cancer by using gefitinib, tamoxifen and etoposide. International Journal of Cancer 120:160-169, 2007. Abstract
Jain M, Venkatraman G, and Batra SK. Optimization of radioimmunotherapy of solid tumors: biological impediments and their modulation. Clinical Cancer Research 13:1374-1382, 2007. Abstract
Mimeault M, Johansson SL, Venkatraman G, Moore E, Henichart JP, Depreux P, Lin MF, and Batra SK. Combined targeting of epidermal growth factor receptor and hedgehog signaling by gefitinib and cyclopamine cooperatively improves the cytotoxic effects of docetaxel on metastatic prostate cancer cells. Molecular Cancer Therapy 6:967-978, 2007. Abstract
Mimeault M, and Batra SK. Functions of tumorigenic and migrating cancer progenitor cells in cancer progression and metastasis and their therapeutic implications. Cancer Metastasis Reviews 26:203-214, 2007. Abstract
Ponnusamy MP, Venkatraman G, Singh AP, Chauhan SC, Johansson SL, Jain M, Smith L, 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 251(2):247-57, 2007. Abstract
Chaturvedi P, Singh AP, Moniaux N, Senapati S, Chakraborty S, Meza JL, and Batra SK. MUC4 Mucin Potentiates Pancreatic Tumor Cell Proliferation, Survival, and Invasive Properties and Interferes with Its Interaction to Extracellular Matrix Proteins. Molecular Cancer Research 5(4):309-20, 2007. (Figure from this MS is on the cover of the April 2007 issue of the Journal) Abstract
Mimeault M and Batra S. Interplay of distinct growth factors during epithelial-mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies. Annals of Oncology 18:1605-1619, 2007. Abstract
Jain M, Venkatraman G, and Batra SK. Cell-penetrating peptides and antibodies: a new direction for optimizing radioimmunotherapy, Eur J Nucl Med Mol Imaging 34(7):973-7, 2007. Abstract
Jain M, Kamal, N, and Batra SK. Engineering antibodies for clinical applications. Trends in Biotechnology 25(7):307-16, 2007. Abstract
Moniaux N, Chaturvedi P, Varshney GC, Meza J, Rodriguez-Sierra JF, Aubert JP, and Batra SK. Human MUC4 mucin induces ultra-structural changes and tumorigenicity in pancreatic cancer cells. Brit J Cancer 97(3):345-57, 2007. Abstract
Andrianifahanana M, Nemos C, Singh AP, Moniaux N, Varshney GC, Mehta PP, and Batra SK. IFN-gamma induced expression of MUC4 in pancreatic cancer cells is mediated by STAT-1 upregulation: A novel mechanism for IFN-gamma response. Oncogene 26:7251-7261, 2007. Abstract
Chaudhary K, Deb S, Moniaux N, Ponnusamy MP, and Batra SK. Human RNA polymerase II-associated factor complex: dysregulation in cancer. Oncogene 26:7499-7507, 2007. Abstract
Mimeault M, Hauke R, and Batra SK. Stem cells: a revolution in therapeutics - recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies. Clinical Pharmacology and Therapeutics 82:252-264, 2007. Abstract
Mimeault M, Hauke R, Mehta PP, and Batra SK. Recent advances in cancer stem/progenitor cell research: Therapeutic implications for overcoming resistance to the most aggressive cancers. Journal of Cellular Molecular Medicine 11:981-1011, 2007. Abstract
Mimeault M, Mehta PP, Hauke R, Henichart JP, Depreux P, Lin MF, and Batra SK. Improvement of cytotoxic efffects induced by mitoxantrone on hormone-refractory metastatic prostate cancer cells by co-targeting epidermal growth facator receptor and hedgehog signaling cascades. Growth Factors 25:400-416, 2007. Abstract
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. 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. Ageing Res Rev, 2008 December 9, Epub ahead of print. 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. 2008; 57:1456-1468. Abstract
Ponnusamy MP, Batra SK. Ovarian cancer: Emerging concept on cancer stem cells. J Ovarian Res. 2008; 1:4. 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. 2008; 23:1541-1552. 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. 2008; 9(11):1076-85. 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. 2008; 68:9231-9238. 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. 2009 Jan 30. [Epub ahead of print] 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. 2009; 125(2)276-285. Abstract
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