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. 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. Metabolic reprogramming promotes tumor cell survival under harsh conditions during transit to distant sites and induces proliferation once the tumor cells establish metastatic loci. MUC16 overexpression is associated with metastatic pancreatic cancer. Our preliminary data demonstrate that compared to the controls, MUC16 expressing pancreatic adenocarcinoma cells take up more glucose, secrete more lactate and reprogram metabolism. Our preliminary studies also identify activation of mTOR, PKM2, and STAT3, and corresponding increase in the expression of c-Myc, a master regulator of metabolic gene expression. We also observed increased motility, invasiveness, and actin cytoskeletal changes in MUC16 expressing cell, in part due to high lactate secretion. Our metabolomics studies show increased glucose flux into aerobic glycolysis, hexosamine biosynthesis pathway and nucleotide biosynthesis, which are regulated by c- myc activity. MUC16-induced lactate production also facilitates expression of Hyaluronan synthase 2 (HAS2). HAS2 together with more substrate, UDP-N-acetylglucosamine from hexosamine biosynthesis pathway, may cause remodeling of extracellular matrix, making it more conducive for the movement of tumor cells. Of particular significance to the proposal, MUC16 is significantly overexpressed by metastatic pancreatic tumors and hence MUC16-induced metabolic reprogramming could be targeted for suppressing metastasis. Our long-term goal is to determine the molecular basis of MUC16-mediated metabolic alterations that facilitate invasiveness and metastasis in pancreatic cancer. Hence, we hypothesize that MUC16-mediated metabolic reprogramming in tumor cells facilitates actin cytoskeletal rearrangements and extracellular matrix remodeling in pancreatic tumors. We further hypothesize that targeting MUC16 or downstream metabolite flux diminishes tumor cell motility, stromal cell survival, and extracellular remodeling to diminish metastasis. Here, we propose to test if blocking MUC16-induced metabolic alterations can suppress metastasis (Aim 1) and if MUC16-induced metabolic changes facilitate metastasis by promoting extracellular matrix remodeling (Aim 2). Furthermore, we propose to decipher the mechanistic basis of MUC16-regulated metabolic alterations and determine the role of c-Myc, mTOR, PKM2, and STAT3 in regulating MUC16- induced metabolic phenotype (Aim 3). These studies will shed light on the metabolic aspects of MUC16- mediated metastasis and may uncover additional therapies for the treatment of metastatic pancreatic cancer.
MUC16, a transmembrane mucin protein, is expressed early in pancreatic cancer pathogenesis and contributes significantly to metastasis. Here, we propose experiments that will explore the role of MUC16 in metabolic reprogramming and the resultant changes in extracellular matrix and cell behavior, which culminate in increased invasiveness and metastasis in pancreatic cancer. Our studies will also provide insights into the mechanism of MUC16-mediated metabolic alterations that facilitate cancer metastasis and will lead to new clinical treatments for human pancreatic cancer.
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