Mechanisms of Homeostasis and Invasive Cell Migration in Skin Tumorigenesis

该提案的长期目标是了解促进和限制生长的信号如何相互作用， 以及它们的失调如何导致肿瘤的发展， 变成恶性的转移癌我的初步数据显示，TGF-β受体11的缺失 （TpRII）功能在皮肤上皮中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 整合素信号在这些癌和培养的角质形成细胞中过度活跃， TpRI 1缺失和FAK激活之间的联系事实上，据报道FAK是最常见的过度激活的 非受体酪氨酸激酶在上皮性肿瘤和肿瘤细胞系中的作用， 分子靶点在很大程度上是未知的。这个提议所检验的中心假设是FAK扮演了一个 在T β Rii缺陷皮肤上皮中SCC的发展中起中心作用。这一假设将得到检验 通过实验：1）评估发展自发肛门和生殖器的概率，或化学 在WT、TpRII和FAK单一和TpRII/FAK双条件突变小鼠的皮肤中诱导SCC， 研究潜在的细胞和病理学改变; 2）分子机制的鉴定 角质形成细胞中TpRII功能的丧失通过其促进FAK活化;以及3）研究角质形成细胞中TpRII功能的丧失如何促进FAK活化。 TpRII和增加的FAK活性促进皮肤癌发生、恶性进展和侵袭性转移。 转移性角质细胞迁移。从拟议的实验中产生的数据将推进我们的研究。 了解TpRII和FAK介导的整合素信号传导在正常人中的分子功能 发展和疾病，确定分子机制，促进生长的Ras和整合素 信号传导与生长限制性TGF-β信号传导相互作用，不仅控制增殖，而且控制细胞 存活、细胞骨架动力学和侵袭性细胞迁移，并鉴定新的分子途径， 甚至在FAK缺乏的情况下也形成癌。总之，这项提案将加强我们的分子 以及细胞对癌变的理解，并将揭示潜在的治疗靶点。.

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-(3 receptor 11 (TpRll) 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 TpRIl loss and FAK activation. Indeed, FAK has been reported to be the most commonly hyperactivated 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 T(3Rii 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, TpRll and FAK single and TpRll/FAK double conditional mutant mice and investigating the underlying cellular and pathological alterations; 2) identification of molecular mechanisms by which loss of TpRll function in keratinocytes promotes FAK activation; and 3) investigate how loss of TpRll and increased FAK activity promote skin carcinogenesis, malignant progression, and invasive metastatic keratinocyte migration. Data generated from the proposed experiments will advance our understanding of the molecular functions of TpRlliand FAK mediated integrin signaling in normal development and disease, identify the molecular mechanisms by which growth promoting Ras and Integrin signaling interact with growth restrictihg TGF-p signaling to control not only proliferation, but also ceil survival, cytoskeletal dynamics and invasive cell migration, and identify novel molecular pathways by which carcinomas form even in the absence of FAK fiintion. Together, this proposal will strengthen our molecular and cellular understanding of carcinoQehesis and will reveal potential therapeutic targets. .