Mechanisms of suppression of colon cancer by receptor tyrosine phosphatase PTPRT

描述（由申请人提供）：本资助的长期目标是阐明受体蛋白酪氨酸磷酸酶PTPRT突变导致结直肠癌发展的机制。这一提议验证了PTPRT突变破坏关键的肿瘤抑制功能，通过破坏细胞-细胞粘附加速肿瘤生长和/或肿瘤进展的假设，以及“信号传感器和转录激活因子3”（STAT3）在PTPRT调节的肿瘤抑制信号通路中起关键作用。本研究的第一个目的是研究PTPRT的肿瘤特异性突变是否会损害培养细胞和胸腺裸鼠异种移植模型的生长抑制功能。第二个目的是确定STAT3是否作为PTPRT调节的细胞信号通路的关键介质，这在肿瘤发展中很重要。第三个目的是确定PTPRT细胞外结构域的肿瘤衍生突变是否会影响细胞-细胞粘附。该建议建立在我们成功利用癌症基因组方法的基础上，该方法系统地探索了蛋白酪氨酸磷酸酶在结直肠癌发展中的潜在作用。我们的初步研究确定了26%的结直肠癌中发生突变的6个酪氨酸磷酸酶基因，为酪氨酸磷酸酶在结直肠癌的发展中发挥关键作用提供了令人信服的证据。PTPRT是六个基因中最常突变的酪氨酸磷酸酶基因，过表达PTPRT可抑制结直肠癌细胞的生长。该实验室最近的工作表明，PTPRT的细胞外结构域介导亲同源结合，这表明PTPRT与其相近的同源物一样，也可能介导细胞-细胞粘附，从而在肿瘤进展中发挥关键作用，因为许多转移性癌症失去了细胞粘附特性。使用一种创新的蛋白质组学方法，我们还确定了STAT3，它在许多癌症中一直被激活，作为PTPRT底物。这些观察结果强调了确定STAT3是否是PTPRT肿瘤抑制信号的关键介质以及肿瘤特异性突变如何影响肿瘤生长和细胞-细胞粘附的重要性。相关性：拟议的研究将扩大我们对导致结肠癌的新因素的理解。这种对结肠癌新靶点的关注应该有助于设计治疗癌症患者的新方法。

DESCRIPTION (provided by applicant): The long term goal of this grant is to elucidate the mechanism through which mutations of receptor protein tyrosine phosphatase PTPRT lead to the development of colorectal cancers. This proposal tests the hypothesis that mutations of PTPRT impair critical tumor suppression functions leading to accelerated tumor growth and/or tumor progression through disrupting cell-cell adhesion and that `signal transducer and activator of transcription 3' (STAT3) plays critical roles in PTPRT regulated tumor suppressor signaling pathways. The first aim of this proposal will investigate whether tumor specific mutations of PTPRT impair growth inhibitory functions in culture cells and in athymic nude mice xenograft models. The second aim will determine whether STAT3 acts as the critical mediator of PTPRT regulated cell signaling pathway that is important in tumor development. The third aim will determine whether tumor-derived mutations in the extracellular domain of PTPRT affect cell-cell adhesion. This proposal builds upon our successful exploitation of a cancer genomic approach that systematically explored the potential roles of protein tyrosine phosphatases in the development of colorectal cancer. Our initial study identified six tyrosine phosphatase genes that are mutated in 26% of colorectal cancers, providing compelling evidence that tyrosine phosphatases play critical roles in the development of colorectal cancers. PTPRT is the most frequently mutated tyrosine phosphatase gene among the six genes and over-expression of PTPRT inhibits growth of colorectal cancer cells. Recent work in this laboratory has now shown that the extracellular domain of PTPRT mediates homophilic binding, suggesting that PTPRT, like its close homologues, may also mediate cell-cell adhesion and thus play a critical role in tumor progression, given the fact that many metastatic cancers lose their cell adhesion properties. Using an innovative proteomic approach, we also identified STAT3, which is consistently activated in many cancers, as a PTPRT substrate. These observations emphasize the importance of determining whether STAT3 is a critical mediator of PTPRT tumor suppressor signaling and how tumor specific mutations affect tumor growth and cell-cell adhesion. Relevance: The proposed study will expand our understanding of new factors that cause colon cancer. This focus on new targets underlying colon cancer should facilitate design of novel approaches to treatment of cancer patients.