Surinder K. Batra

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

Surinder K. Batra

Phone: 402-559-5455 (Office)
402-559-7754 (Lab)
402-321-5936 (Cell)
402-559-6650 (Fax)
Email

Education/Training:

Ph.D., Kurukshetra University (NDRI), INDIA, 1983

Stragier, L’institut national de la recherché agronomique (INRA)
Tours, France, 1982-83

Post-doctoral Fellow, North Carolina State University, Raleigh, NC, USA, 1983-1986

Research Associate Post-doctoral Fellow,  Duke University Medical Center, Durham, USA, 1988-1991

Research:

Student research opportunities in my lab:
Graduate Students
Medical Students, Summer Research Students,
Undergraduate students.

Primary Research/Clinical Interests/Expertise:
Mucins, 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.

Schematic representation of MUC4 gene, mRNA and protein

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).

Schematic representation of the modular structure of MUC4

Currently, we are working on:

  1. Defining the mechanism(s) responsible for MUC4-mediated regulation of EGFR members in pancreatic and other cancer cells.
  2. Determining the molecular mechanisms by which MUC4 contributes to tumor growth and metastasis.
  3. Investigating the co-operative action of MUC4 in combination with other defined oncogenic mutations, in the early development of 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:

  1. 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.
  2. Understanding the dysregulation of PD2/hPaf 1 and hPAF1 complex in cancers.
  3. Molecular and biochemical studies on PDF/MIC-1.
  4. PP2A-mediated oncogenesis

Publications:

My Publications


Current Grants and Contracts:
 

2018-2023

PO1 CA217798
Principal Investigators: Surinder K. Batra
Title: Pancreatic cancer metastasis

2018-2021

PC170891 (DoD)
Principal Investigators: Surinder K. Batra and Rakesh Kukreja
Title: PDE5 Inhibitor (Sildenafil) for Ameliorating Androgen-Deprivation Therapy (ADT)–Induced Cardiotoxicity
Role on the project: MPI

2018-2023

RO1 CA 228524 (NIH) (MPI)
Principal Investigators:  Rakesh K. Singh and Surinder K. Batra
Title: Targeting CXCR2 axis in Pancreatic Cancer

2017-2022

RO1 CA 210637 (NIH) (MPI)
Principal Investigators: Moorthy P. Ponnusamy and Surinder K. Batra
Title: Role of PD2/Paf1 in Pancreatic Acinar to Ductal Metaplasia

2017-2022

UO1 CA 210240
Principal Investigator: Michael Hollinswoth
Title: Pancreatic cancer consortium
Role on the project: Co.Investigaor (subcontract)

2016-2021

R01 CA 206444
Principal Investigators: Michel Ouellette and Surinder K. Batra
Title: Rac1 GTAase in tumorigenesis and metastasis of pancreatic cancer

2016-2021

U01 CA 200466         (NIH) (MPI)
Principal Investigators: Randall Brand and Surinder K. Batra
Title: Validation of biomarkers for early diagnosis and risk prediction of pancreatic neoplasms

2015-2020

UO1 CA185148 01 (NIH)
Principal Investigators: Surinder K. Batra
Title: MIC-1 and its functional partners in prostate cancer racial disparity

2014-2019

RO1 CA183459 (NIH)
Principal Investigator: Surinder K. Batra
Title: Targeting Mucin and EGFR Axis in Pancreatic Cancer

2015-2020

R01 CA195586-01 (NIH) (MPI)
Principal Investigators: Surinder K. Batra and Maneesh Jain
Title: Targeted radiation therapy of pancreatic cancer