Mechanisms of homeostasis and invasive cell migration in skin tumorigenesis

描述（由申请人提供）：本提案的长期目标是了解生长促进和限制信号如何相互作用以相互平衡，以及它们的失调如何导致经常转变为恶性转移癌的赘生性肿瘤的发展。我的初步数据显示，皮肤上皮中TGF-β受体II（T（3RII））功能的丧失产生自发性肛门和生殖器鳞状细胞癌（SCC），并与活性H-Ras合作形成转移性SCC。粘着斑激酶（FAK）介导的整合素信号传导在这些癌和培养的角质形成细胞中过度活跃，表明TfiRII损失和FAK活化之间的直接联系。事实上，已经报道FAK是上皮肿瘤和肿瘤细胞系中最常见的超活化非受体酪氨酸激酶，但其功能和分子靶点在很大程度上是未知的。该提议检验的中心假设是FAK在TpRII缺陷皮肤上皮中SCC的发展中起核心作用。1）评估在WT、JftRII和FAK单条件突变小鼠和TJ 3RII/FAK双条件突变小鼠的皮肤中发展自发性肛门和生殖器SCC或化学诱导SCC的概率，并研究潜在的细胞和病理学改变; 3）研究TpRII的丧失和FAK活性的增加如何促进皮肤癌发生、恶性进展，和侵袭性转移性角质形成细胞迁移;和2）鉴定角质形成细胞中TfSRI 1功能丧失促进FAK活化的分子机制。从所提出的实验产生的数据将促进我们对TPRII和FAK介导的整合素信号传导在正常发育和疾病中的分子功能的理解，鉴定生长促进Ras和整合素信号传导与生长限制TGF-β信号传导相互作用以不仅控制增殖，而且控制细胞存活、细胞骨架动力学和侵入性细胞迁移的分子机制，并识别即使在缺乏FAK功能的情况下也会形成癌症的新分子途径。总之，这一提议将加强我们对致癌作用的分子和细胞理解，并将揭示潜在的治疗靶点。

DESCRIPTION (provided by applicant): The long term goal of this proposal is to understand how growth promoting and restricting signals interact to balance one another and how their deregulation leads to the development of neoplastic tumors which often turn into malignant, metastatic carcinomas. My preliminary data revealed that loss of TGF-p receptor II (T(3RII) function in the skin epithelium produces spontaneous anal and genital squamous cell carcinomas (SCCs) and cooperates with active H-Ras to form metastatic SCCs. Focal adhesion kinase (FAK) mediated integrin signaling is hyperactive in these carcinomas and cultured keratinocytes suggesting a direct link between TfiRII loss and FAK activation. Indeed, FAK has been reported to be the most commonly hyper- activated non receptor tyrosine kinase in epithelial tumors and tumor cell lines, yet its functions and molecular targets are largely unknown. The central hypothesis tested by this proposal is that FAK plays a central role in the development of SCCs in TpRII deficient skin epithelium. This hypothesis will be tested experimentally by: 1) assessing the probabilities to develop spontaneous anal and genital, or chemically induced SCCs in skin of WT, JftRII and FAK single and TJ3RII/FAK double conditional mutant mice and investigating the underlying cellular and pathological alterations; 3) investigate how loss of TpRII and increased FAK activity promote skin carcinogenesis, malignant progression, and invasive metastatic keratinocyte migration; and 2) identification of molecular mechanisms by which loss of TfSRIlfunction in keratinocytes promotes FAK activation. Data generated from the proposed experiments will advance our understanding of the molecular functions of TPRII and FAK mediated integrin signaling in normal development and disease, identify the molecular mechanisms by which growth promoting Ras and Integrin signaling interact with growth restricting TGF-P signaling to control not only proliferation, but also cell survival, cytoskeletal dynamics and invasive cell migration, and identify novel molecular pathways by which carcinomas form even in the absence of FAK function. Together, this proposal will strengthen our molecular and cellular understanding of carcinogenesis and will reveal potential therapeutic targets.