Project 3: MUC16-Mediated Metabolic Reprograming Induces PC Metastasis

项目概述：胰腺癌是最致命的癌症之一，因为其广泛的 即使在肿瘤的早期阶段，也会侵入周围组织并转移到远处器官 进展因此，对这些肿瘤的生物学和促进肿瘤生长的机制的基本了解是必要的。 其侵袭和转移将为开发新的诊断和治疗方法提供基础。 肿瘤细胞表现出代谢改变，导致肿瘤生长或转移增强。代谢 重编程促进肿瘤细胞在运输到远处的苛刻条件下存活，并诱导 一旦肿瘤细胞建立了转移位点，细胞就会增殖。MUC 16过表达与 转移性胰腺癌我们的初步数据表明，与对照组相比，MUC 16 表达的胰腺癌细胞摄取更多的葡萄糖，分泌更多的乳酸， 新陈代谢.我们的初步研究还确定了mTOR，PKM 2和STAT 3的激活，以及相应的 代谢基因表达的主要调节因子c-Myc的表达增加。我们还观察到 MUC 16表达细胞的运动性、侵袭性和肌动蛋白细胞骨架变化增加，部分原因是 高乳酸分泌。我们的代谢组学研究表明，增加葡萄糖通量进入有氧 糖酵解、己糖胺生物合成途径和核苷酸生物合成，这是由c- myc活性MUC 16诱导的乳酸产生也促进了Hybryonan合成酶2（HAS 2）的表达。 HAS 2与更多的底物，来自己糖胺生物合成途径的UDP-N-乙酰葡糖胺一起，可以 引起细胞外基质的重塑，使其更有利于肿瘤细胞的运动。的 特别重要的是，MUC 16在转移性胰腺肿瘤中显著过表达， 因此MUC 16诱导的代谢重编程可以靶向抑制转移。 我们的长期目标是确定MUC 16介导的代谢改变的分子基础， 促进胰腺癌的侵袭和转移。因此，我们假设MUC 16介导的 肿瘤细胞中的代谢重编程促进肌动蛋白细胞骨架重排， 胰腺肿瘤中的基质重塑我们进一步假设，靶向MUC 16或下游 代谢物通量减少肿瘤细胞运动性、基质细胞存活和细胞外重塑， 减少转移。在这里，我们建议测试阻断MUC 16诱导的代谢改变是否可以抑制 转移（目的1），以及MUC 16诱导的代谢变化是否通过促进细胞外 基质重塑（目标2）。此外，我们建议破译MUC 16调节的机制基础， 代谢改变，并确定c-Myc，mTOR，PKM 2和STAT 3在调节MUC 16- 诱导代谢表型（Aim 3）。这些研究将阐明MUC 16的代谢方面， 介导的转移，并可能揭示用于治疗转移性胰腺癌的其他疗法。

Project Summary: 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.