MUC1 regulation of TGF-beta function in pancreatic cancer cells

描述（由申请人提供）：胰腺癌是一种毁灭性的疾病，平均生存期为3-6个月。这种疾病的特征是高度侵袭性的肿瘤，对标准化疗和放疗有抵抗力。MUC 1是一种跨膜粘蛋白糖蛋白，在超过60%的人胰腺癌（PDA）中显著增加和差异糖基化。此外，MUC 1是侵袭性PDA的标志物，因为其表达与高转移、耐药性和预后不良相关。然而，MUC 1相关攻击性的潜在机制仍不清楚。我们有新的初步证据表明，PDA细胞，不表达MUC 1发生凋亡，在响应TGF-？而表达MUC 1的PDA细胞在TGF-β诱导下发生EMT和侵袭。TGF-？-当MUC 1的胞质尾区（MUC 1 CT）突变时，诱导的侵袭完全丧失。因此，通过MUC 1 CT的信号转导对于TGF-β-导致入侵发生。TGF-？是癌发生的主要参与者，并且以其在胰腺癌中作为肿瘤抑制剂和肿瘤促进剂的矛盾作用而闻名。了解驱动TGF-β的因素和信号？从肿瘤抑制因子转换为肿瘤促进因子的功能引起了人们极大的兴趣。我们假设通过MUC 1-CT的信号传导支持TGF-β-诱导EMT和侵袭并抑制TGF-β-诱导凋亡。具体目的是：1）确定TGF-？诱导EMT的MUC 1+，MUC 1-，和MUC 1+细胞，其中MUC 1 CT中的酪氨酸残基已突变为苯丙氨酸（MUC 1 Y 0）; 2），以确定TGF-？诱导MUC 1+、MUC 1-和MUC 1 Y 0细胞凋亡。为此，提出了体外和体内实验。如果假设是真的，这将是第一次证明MUC 1作为一个开关， PDA细胞，改变促凋亡的TGF-？抗凋亡和促存活的特性。所获得的知识将不得不考虑在开发未来的治疗，旨在针对肿瘤促进信号的TGF-？同时仍保留TGF-β的促凋亡信号。到目前为止，MUC 1治疗集中在MUC 1的细胞外区域，这还没有导致临床成功。如果这一假设成立，那么开发专门针对MUC 1 CT信号的药物应该成为优先事项。

DESCRIPTION (provided by applicant): Pancreatic cancer is a devastating disease with dismal median survival of 3-6 months. The disease is characterized by highly aggressive tumors that are resistant to standard chemo and radiation therapies. MUC1 is a transmembrane mucin glycoprotein that is significantly increased and differentially glycosylated in over 60% of human pancreatic adenocarcinomas (PDA). Further, MUC1 is a marker of aggressive PDA, as its expression is correlated with high metastases, drug resistance, and poor prognosis. However, the underlying mechanisms of MUC1 associated aggressiveness remain unclear. We have new preliminary evidence that PDA cells that do not express MUC1 undergo apoptosis in response to TGF-? whereas PDA cells that express MUC1 undergo EMT and invasion in response to TGF-?. The TGF-?-induced invasion is completely lost when the cytoplasmic tail of MUC1 (MUC1 CT) is mutated. Therefore signal transduction through MUC1 CT is necessary for TGF-?-induced invasion to occur. TGF-? is a major player in carcinogenesis, and is well known for its paradoxical role as both a tumor suppressor and a tumor promoter in pancreatic cancer. Understanding the factors and signals that drive TGF-? function to switch from tumor-suppressor to tumor-promoter is of great interest. We hypothesize that signaling through MUC1-CT supports TGF-?-induced EMT and invasion and inhibits TGF-?-induced apoptosis. The specific aims are: 1) to determine the differential effects of TGF-? induced EMT in MUC1+, MUC1-, and MUC1+ cells in which the tyrosine residues in the MUC1 CT have been mutated to phenylalanine (MUC1 Y0); 2) to determine the differential effects of TGF-? induced apoptosis in MUC1+, MUC1-, and MUC1 Y0 cells. Both in vitro and in vivo experiments are proposed for the aims. If the hypothesis is true, this will be the first demonstration that MUC1 acts as a switch in PDA cells, changing the pro-apoptotic property of TGF-? to an anti-apoptotic and pro-survival property. The knowledge gained will have to be considered when developing future therapies that aim to target the tumor promoting signals of TGF-? while still retaining the pro-apoptotic signals of TGF-?. So far, MUC1 therapeutics has focused on the extracellular region of MUC1 which has not led to clinical success. If the hypothesis holds true, then developing drugs that specifically target MUC1 CT signaling should become a priority.