Professor, Eppley Institute
Department of Biochemistry and Molecular Biology
Tel: 402-559-2726 (Office)
Honors and Awards
2013-2015 Pancreatic Cancer Action Network-AACR Career Development Award
2013-2016 DoD Idea Award
2012 Outstanding Performance Award from UNMC
2010-2013 Pancreatic cancer SPORE Career Development Award
2007 Thomas Jefferson Ingenuity Award
2007 Harris Award for Cancer Research
2006 Selected as American Association for Advancement of Science (AAAS) member through AAAS/Science Program for Excellence in Science
2006 American Society for Cell Biology Travel Award for ASCB Annual Meeting
2006 MSBRF Best Presentation Award
2006 Eppley Institute Best Presentation Award
2006 Graduate Studies Best Presentation Award
2005 Biochemistry and Molecular Biology Department Best Presentation Award
2002-2006 Graduate Student Research Fellowship
2001-2002 Department of Biotechnology, Government of India-Junior Research Fellow at National Institute of Immunology
2001 Council for Scientific and Industrial Research, India-Junior Research Fellowship (ranked in top 20%)
Currently recruiting new students
- Signaling networks regulating cancer metabolism
- Systems Biology approach (utilizing genomics/proteomics/metabolomics) to elucidate metabolic networks regulating survival, proliferation, and chemosensitivity of tumor cells
- Tumor-stromal metabolic interactions
- Genome-wide miRNA screens to investigate the role of tumor microenvironment
- Metabolic regulations in cancer stem cells
Cancer cells demonstrate an increase in aerobic glycolysis and shunted flux of metabolites through TCA cycle. This phenomenon is called the Warburg effect. My laboratory has broad interests in the metabolic regulations that support tumor growth, help the tumor cells survive under harsh conditions, facilitate metastasis and impart resistance to chemotherapies. For our studies we utilize molecular biology tools, NMR/MS-based metabolomics and proteomics, high-throughput expression arrays, next-generation sequencing, cell-based assays, and animal models.
Pancreatic adenocarcinomas are among the most fatal malignancies because of their extensive invasion into surrounding tissues and metastasis to distant organs, even at an early stage of tumor progression. The poor prognosis of this malignancy also reflects a generally poor response to current therapies. Thus, a basic understanding of the biology of these tumors and the mechanisms that promote their invasion and metastasis will provide a basis for developing new methods for diagnosis and treatment. Tumor cells display metabolic alterations that result in enhanced tumor growth, metastasis or resistance to chemotherapy. Enhanced aerobic glycolysis and metabolite flux into biosynthetic reactions in tumor cells facilitate tumor-stromal metabolite cross talk and tumor aggressiveness. MUC1 overexpression is associated with aggressive (invasive and metastatic) forms of pancreatic and other cancers. Our studies demonstrate that MUC1 expressing pancreatic adenocarcinoma cells take up more glucose and secrete more lactate than the control cells. We also identified a number of key metabolic genes, whose promoter elements are physically occupied and expression is enhanced by MUC1. Furthermore, pancreatic tumors are highly hypoxic and hypoxia leads to the stabilization of the hypoxia inducible factor-1 alpha (HIF-1a), the master regulator of metabolism in cancer. Research from our laboratory has shown that the stability and activity of HIF-1a is regulated by MUC1. Our studies indicate that MUC1 physically interacts with HIF-1α and its co-activator p300 and increases the recruitment of HIF-1α and p300 onto glycolytic gene promoters. Furthermore, MUC1 also stabilizes HIF-1α protein by reducing the intracellular levels of alpha-ketoglutarate. Importantly, MUC1 is overexpressed by most pancreatic tumors and hence, MUC1-induced tumor-stromal metabolic cross talk could be targeted for suppressing growth and invasiveness, and improving gemcitabine sensitivity in pancreatic cancer. Our long-term goal is to determine the molecular basis of MUC1-mediated metabolic alterations that facilitate invasiveness and metastasis in pancreatic cancer.
A major project in the lab aims to determine the metabolic interrelationship of pancreatic cancer cells with their surrounding microenvironment. Tumor cells take up increased amount of lactate and this lactate can increase desmoplasia, i.e. increased stromal tissue. The stroma has been shown to protect and nourish the tumor, and create treatment resistance by impeding drug delivery. We are currently investigating how the tumor cells protect the stromal cells and facilitate desmoplasia by metabolically supplementing their energy needs.
Gemcitabine is the current standard of care for pancreatic cancer. However, most pancreatic tumors are resistant to this treatment. Gemcitabine, a cytidine analogue, functions by blocking DNA synthesis in cells that are actively dividing. We are investigating, for the first time, the link between tumor metabolism and gemcitabine resistance in pancreatic cancer. This projects aims to investigate if alterations in metabolite flux through major biosynthetic pathways impart chemotherapy resistance to pancreatic cancer cells. By combining transcriptomics, metabolomics and proteomics we aim to identify the signaling networks that impart chemotherapy resistance to tumor cells.
Other important projects include determining the metabolic regulation of cachexia in pancreatic cancer and the role of microRNAs in pancreatic cancer metabolism.
Award Period: 2013-2016