Targeting MUC1-induced Tumor-stromal Metabolic Cross-talk in Pancreatic Cancer

描述（由申请人提供）：胰腺腺癌是最致命的癌症之一，因为它们广泛侵入周围组织并转移到远处器官，即使在肿瘤进展的早期阶段。这种恶性肿瘤的预后差也反映了对目前治疗的反应普遍较差。因此，对这些肿瘤的生物学以及促进其侵袭和转移的机制的基本了解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。肿瘤细胞中有氧糖酵解和代谢物流入生物合成反应的增强促进肿瘤-基质代谢物串扰和肿瘤侵袭性。MUC 1过表达与胰腺癌和其他癌症的侵袭性（侵袭性和转移性）形式相关。我们的初步研究表明，表达MUC 1的胰腺癌细胞比对照细胞吸收更多的葡萄糖并分泌更多的乳酸。我们的初步研究还确定了一些关键的代谢基因，其启动子元件被物理占据，MUC 1增强了表达，这表明MUC 1对癌细胞代谢具有潜在的转录调控作用。此外，我们的数据表明MUC 1促进低氧诱导因子1 α的活性/稳定性增强，低氧诱导因子1 α是癌细胞糖酵解的关键调节因子。对于本申请特别重要的是，MUC 1被大多数胰腺肿瘤过表达，因此MUC 1诱导的肿瘤-基质代谢串扰可以被靶向用于抑制胰腺癌中的生长和侵袭性，并改善吉西他滨敏感性。我们的长期目标是确定MUC 1介导的促进胰腺癌侵袭和转移的代谢改变的分子基础。在这里，我们假设，通过MUC 1信号稳定HIF 1？并促进胰腺癌中上皮和基质成分之间的代谢串扰;从而促进肿瘤进展和转移。此外，我们提出，阻断MUC 1介导的上皮和间质成分之间的代谢串扰将减少胰腺癌的肿瘤进展和转移。为了验证这些假设，我们提出测试MUC 1在调节肿瘤-基质代谢串扰（Aim 1）和调节HIF稳定/活性（Aim 2）中的作用，以及选择性阻断MUC 1诱导的肿瘤-基质代谢串扰（Aim 1）在逆转胰腺癌中MUC 1介导的侵袭性和化疗耐药性中的治疗功效。我们还提出了代谢组学研究，以确定MUC 1调节的代谢产物，并确定其生物合成基因在临床标本中的表达（目的3）。这些研究将阐明MUC 1介导的肿瘤进展的代谢方面，并可能揭示胰腺癌治疗的其他治疗策略。 公共卫生相关性：表达MUC 1的胰腺癌比MUC 1无效肿瘤更具侵袭性和转移性。在这里，我们提出的实验，将探讨MUC 1在肿瘤间质代谢串扰在胰腺癌在转录和生理水平的作用。我们的研究将为MUC 1介导的促进癌症进展的代谢改变机制提供见解，并将为人类胰腺癌带来新的临床治疗方法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.