Mechanisms of Homeostasis and Invasive Cell Migration in Skin Tumorigenesis

皮肤肿瘤发生中的稳态和侵袭细胞迁移机制

• 批准号: 8517009
• 负责人: Markus Schober
• 金额: $ 23.65万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517009
• 关键词: Anus; Apoptosis; Automobile Driving; Benign; Candidate Disease Gene; Carcinoma; Cell Survival; Cell-Matrix Junction; Cells; Data; Development; Disease; Disseminated Malignant Neoplasm; Epidermis; Epithelial; Epithelium; Equilibrium; Focal Adhesion Kinase 1; Focal Adhesions; Gene Expression; Genes; Genital system; Goals; Growth; Growth Factor; HRAS gene; Homeostasis; Human; Instruction; Integrins; Lead; Link; Literature; Malignant - descriptor; Malignant Conversion; Malignant Neoplasms; Mediating; Metastatic Carcinoma; Metastatic Squamous Cell Carcinoma; Molecular; Molecular Target; Mus; Mutant Strains Mice; Neoplasm Metastasis; Pathway interactions; Play; Probability; Proteomics; Receptor Protein-Tyrosine Kinases; Reporting; Role; Signal Transduction; Skin; Skin Carcinogenesis; Skin Carcinoma; Squamous cell carcinoma; Technology; Testing; Therapeutic; Tissues; Transcription Factor 3; Transducers; Tumor Cell Line; Tumor Markers; Tumor Suppressor Genes; Tyrosine; adhesion receptor; base; carcinogenesis; cell motility; combinatorial; human disease; keratinocyte; migration; neoplastic; novel; novel therapeutic intervention; prevent; programs; receptor; research study; therapeutic target; tumor; tumor initiation; tumor progression; tumorigenesis

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. .

该提议的长期目标是了解增长和限制信号如何相互作用 平衡彼此，以及他们的放松管制如何导致肿瘤肿瘤的发展 变成恶性转移性癌。我的初步数据表明，TGF-的丢失（3受体11 （TPRLL）皮肤上皮的功能会产生自发的肛门和生殖器鳞状细胞癌 （SCC）并与主动H-RAS合作形成转移性SCC。局灶性粘附激酶（FAK）介导 整联蛋白信号传导在这些癌和培养的角质形成细胞中表明直接链接 在Tpril损失和FAK激活之间。确实，据报道FAK是最常见的过度活化 上皮肿瘤和肿瘤细胞系中的非受体酪氨酸激酶，但其功能和 分子靶标在很大程度上未知。该提议检验的中心假设是FAK扮演 t（3RII缺乏皮肤上皮的SCC的发展中的中心作用。将检验该假设 实验：1）评估发展自发肛门和生殖器或化学的概率 WT，TPRLL和FAK单一和TPRLL/FAK双条件突变小鼠的诱导SCC， 研究潜在的细胞和病理改变； 2）鉴定分子机制 在角质形成细胞中，TPRLL功能的丧失促进了FAK激活； 3）调查如何损失 TPRLL和增加的FAK活性促进皮肤致癌，恶性进展和侵入性 转移性角质形成细胞迁移。从建议的实验产生的数据将推动我们的 理解正常中Tprlliand FAK介导的整联蛋白信号的分子功能 发育和疾病，确定促进RAS和整联蛋白的分子机制 信号传导与生长限制TGF-P信号传导相互作用，不仅控制增殖，还可以控制CEIL 生存，细胞骨架动力学和侵入性细胞迁移，并确定新的分子途径 即使没有Fak Fiintion，也形成了癌。该提议将加强我们的分子 和细胞对Carcinoqehesis的理解，并将揭示潜在的治疗靶标。 。