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疾病，中位生存期为3-6个月。该疾病的特点是高度侵袭性肿瘤，对标准的化疗和放疗具有耐药性。MUC1是一种跨膜粘蛋白糖蛋白，在超过60%的人胰腺腺癌（PDA）中显著升高和差异糖基化。此外，MUC1是侵袭性PDA的标志物，其表达与高转移、耐药和不良预后相关。然而，MUC1相关侵袭性的潜在机制尚不清楚。我们有新的初步证据表明，不表达MUC1的PDA细胞在TGF-？而表达MUC1的PDA细胞则会响应TGF-?进行EMT和侵袭。TGF - ?当MUC1的细胞质尾部（MUC1 CT）发生突变时，-诱导的侵袭完全丧失。因此通过MUC1 CT的信号转导是TGF-？-诱导入侵发生。TGF - ?是一个主要的参与者在癌变，并众所周知，其矛盾的作用，作为肿瘤抑制和肿瘤启动子在胰腺癌。了解驱动TGF-？从肿瘤抑制因子到肿瘤启动因子的转换功能引起了人们的极大兴趣。我们假设通过MUC1-CT的信号支持TGF-？诱导EMT和侵袭并抑制TGF-？全身的细胞凋亡。具体目的是：1)确定TGF-？在MUC1+、MUC1-和MUC1+细胞中诱导EMT，其中MUC1 CT中的酪氨酸残基突变为苯丙氨酸（MUC1 Y0）；2)确定TGF-？诱导MUC1+、MUC1-和MUC1 Y0细胞凋亡。提出了体外和体内实验的目的。如果这个假设是正确的，这将是MUC1作为一个开关的第一次证明

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.