MUC1 regulation of TGF-beta function in pancreatic cancer cells

描述(申请人提供)：胰腺癌是一种破坏性疾病，中位生存期为3-6个月。这种疾病的特点是高度侵袭性的肿瘤，对标准的化疗和放射治疗具有抵抗力。MUC1是一种跨膜粘蛋白糖蛋白，在超过60%的人胰腺癌(PDA)中显著增加并分化为糖基化。此外，MUC1是侵袭性PDA的标志，因为它的表达与高转移、耐药和预后不良相关。然而，MUC1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，不表达MUC1的PDA细胞在转化生长因子？而表达MUC1的PDA细胞则在转化生长因子-β的作用下发生EMT和侵袭。当MUC1(MUC1CT)的胞浆尾部发生突变时，由转化生长因子β诱导的侵袭完全消失。因此，通过MUC1CT的信号转导对于转化生长因子β诱导的侵袭的发生是必要的。转化生长因子-？在胰腺癌的发生过程中起着重要的作用，并且在胰腺癌中既是肿瘤抑制因子又是肿瘤促进剂而广为人知。了解驱动转化生长因子的因素和信号？从肿瘤抑制者到肿瘤促进者的功能转换是人们非常感兴趣的问题。我们假设，通过MUC1-CT传递的信号支持转化生长因子β诱导的EMT和侵袭，并抑制转化生长因子β诱导的细胞凋亡。具体目的是：1)确定转化生长因子-？在MUC1CT中酪氨酸残基突变为苯丙氨酸(MUC1Y0)的MUC1+、MUC1-和MUC1+细胞中诱导EMT：2)确定转化生长因子-？诱导MUC1+、MUC1-和MUC1Y0细胞的凋亡。体外和体内实验都是为了这些目的而提出的。如果假设是真的，这将是MUC1充当开关的第一个证明 PDA细胞，改变转化生长因子-2的促凋亡特性？一种抗凋亡和有利于生存的特性。在开发以转化生长因子促进肿瘤信号为靶点的未来疗法时，必须考虑所获得的知识。同时仍保留促凋亡信号的转化生长因子-β。到目前为止，MUC1的治疗主要集中在MUC1的胞外区域，但尚未取得临床成功。如果假设成立，那么开发专门针对MUC1CT信号的药物应该成为当务之急。

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.