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

描述(申请人提供)：胰腺癌是最致命的癌症之一，因为它广泛侵犯周围组织并转移到远处器官，即使在肿瘤进展的早期也是如此。这种恶性肿瘤的预后不佳也反映了对当前治疗的普遍反应不佳。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变化，导致肿瘤生长或转移增强。增强肿瘤细胞中有氧糖酵解和代谢产物进入生物合成反应的流量有助于肿瘤-间质代谢产物的串扰和肿瘤的侵袭性。MUC1的过度表达与侵袭性(侵袭性和转移性)形式的胰腺癌和其他癌症有关。我们的初步研究表明，表达MUC1的胰腺癌细胞比对照细胞摄取更多的葡萄糖和分泌更多的乳酸。我们的初步研究还发现了一些关键的代谢基因，其启动子元件被物理占据，其表达被MUC1增强，表明MUC1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，MUC1促进低氧诱导因子1α的活性/稳定性增强，该因子是癌细胞糖酵解的关键调节因子。对于目前的应用特别重要的是，MUC1在大多数胰腺肿瘤中过表达，因此MUC1诱导的肿瘤间质代谢串扰可能被靶向抑制胰腺癌的生长和侵袭性，并提高吉西他滨的敏感性。我们的长期目标是确定促进胰腺癌侵袭和转移的MUC1介导的代谢改变的分子基础。在这里，我们假设通过MUC1的信号稳定HIF1？？，并促进胰腺癌上皮和间质成分之间的代谢串扰，从而促进肿瘤的进展和转移。此外，我们认为阻断MUC1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。为了验证这些假说，我们建议测试MUC1在调节肿瘤-间质代谢串扰(Aim 1)和调节HIF稳定/活性(Aim 2)中的作用，以及选择性阻断MUC1诱导的肿瘤间质代谢串扰(Aim 1)在逆转MUC1介导的胰腺癌侵袭性和化疗耐药性方面的疗效。我们还建议进行代谢组学研究，以确定MUC1调节的代谢物，并确定其生物合成基因在临床标本中的表达(目标3)。这些研究将阐明MUC1介导的肿瘤进展的代谢方面，并可能发现治疗胰腺癌的其他治疗策略。

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.