Pancreatic adenocarcinomas are among the most fatal cancers 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 or metastasis. Enhanced aerobic glycolysis and metabolite flux into biosynthetic reactions in tumor cells facilitates tumor-stromal metabolite cross-talk and tumor aggressiveness. MUC1 overexpression is associated with aggressive (invasive and metastatic) forms of pancreatic and other cancers. We have preliminary studies showing that MUC1 expressing pancreatic adenocarcinoma cells take up more glucose and secrete more lactate than control cells. Our preliminary studies also identify number of key metabolic genes, whose promoter elements are physically occupied and expression is enhanced by MUC1, suggesting a potential transcriptional regulation of cancer cell metabolism by MUC1. Furthermore, our data indicate that MUC1 facilitates enhanced activity/stabilization of hypoxia-inducible factor 1 alpha, which is a key regulator of glycolysis n cancer cells. Of particular significance to the current application, 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. Here, we hypothesize that signaling through MUC1 stabilizes HIF1??and facilitates metabolic cross-talk between epithelial and stromal components in pancreatic adenocarcinoma; thus facilitating tumor progression and metastasis. Furthermore, we propose that blocking MUC1-mediated metabolic cross-talk between epithelial and stromal components will reduce tumor progression and metastasis in pancreatic cancer. To test these hypotheses, we propose to test the role of MUC1 in modulating tumor-stromal metabolic cross-talk (Aim 1) and in regulating HIF stabilization/activity (Aim 2), and therapeutic efficacy of selectively blocking MUC1 induced tumor-stromal metabolic cross-talk (Aim 1) in reversing MUC1-mediated aggressiveness and chemotherapy resistance in pancreatic cancer. We also propose metabolomic studies to identify MUC1-regulated metabolites and to determine the expression of their biosynthetic genes in clinical specimens (Aim 3). These studies will shed light on the metabolic aspects of MUC1-mediated tumor progression and may uncover additional therapeutic strategies for the treatment of pancreatic cancer.
MUC1-expressing pancreatic cancers are more aggressive and more metastatic than MUC1 null tumors. Here, we propose experiments that will explore the role of MUC1 in tumor-stromal metabolic cross-talk in pancreatic cancer at both transcriptional and physiological levels. Our studies will provide insights into the mechanism of MUC1-mediated metabolic alterations that facilitate cancer progression and will lead to new clinical treatments for human pancreatic cancer.
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