KY COBRE: TALIN-1 METASTISIS SUPPRESSOR IN LUNG CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 肺癌是一种多因素疾病，由一系列遗传事件引起，包括细胞周期检查点和进展、细胞增殖和染色体稳定性的变化，从而导致原发癌的发展。在原发肿瘤建立后，正常的细胞黏附和运动的变化随后允许这些肿瘤细胞逃离原始肿瘤，迁移到次要部位，并重新生长。在原发肿瘤中获得这种能力通常会导致临床上无法治愈的疾病，而这些继发肿瘤或转移瘤是导致肺癌患者死亡率和发病率的重要因素。9号染色体上9p21位的几个基因损伤与肺癌有关。其中包括焦点黏附蛋白Talin-1，它与细胞黏附和运动有关。某些肺癌细胞中Talin-1水平降低。 需要评估的假设是Talin-1的失调导致细胞黏附改变，从而导致原发肿瘤中细胞的锚定无关生长。这种表型的获得会增加这些细胞的侵袭力，导致转移性肺癌的发生。 明确的目标。这一假说将通过以下方式解决：(1)在基因、mRNA和蛋白质水平上确定肺癌细胞Talin-1缺失的分子基础；(2)确定Talin-1在肺癌细胞黏附、迁移和侵袭中的作用，特别是关注肺癌细胞在模拟体内细胞环境的三维培养基质中的行为；(3)将这些研究扩展到代表肺癌各个组织学类别的广泛的肺癌细胞系，以便确定转移性肺癌的先前未知的一般特征。 意义重大。这些研究将深入了解肺癌进展的分子和细胞机制，并确定Talin-1是否为肺癌转移的抑制因子。这些研究还将导致开发治疗转移性肺癌的新的预后指标和治疗策略。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lung cancer is a multifactorial disease caused by a cascade of genetic events, including changes in cell cycle checkpoint and progression, cell proliferation, and chromosome stability, which leads to the development of a primary carcinoma. After establishment of the primary tumor, changes in normal cell adhesion and motility subsequently allow these tumor cells to escape from the original tumor, migrate to secondary sites, and grow anew. The acquisition of this capacity in the primary tumor frequently results in clinically incurable disease, and these secondary tumors, or metastases, are a significant contributor to mortality and morbidity in lung cancer patients. Several genetic lesions on chromosome 9 at position 9p21 have been associated with lung cancer. Among these is the focal adhesion protein Talin-1, which is involved in cell adhesion and motility. Talin-1 levels are decreased in certain lung cancer cells. The HYPOTHESIS to be evaluated is that dysregulation of Talin-1 leads to altered cell adhesion leading to anchorage-independent growth of cells in the primary tumor. Acquisition of this phenotype then increases the invasiveness of these cells and results in the development of metastatic lung cancer. SPECIFIC AIMS. This hypothesis will be addressed by (1) determining the molecular basis for the Talin-1 deficiency at the gene, mRNA, and protein levels in lung cancer cells; (2) determining the role of Talin-1 in lung cancer cell adhesion, migration, and invasion, with particular emphasis on the behavior of lung cancer cells in three-dimensional culture matrices that mimic the cellular environment in vivo; and (3) extending these studies to a broad panel of lung cancer cell lines representing each histological class of lung cancer so that previously unknown general features of metastatic lung cancer will be identified. SIGNIFICANCE. These studies will provide insight into the molecular and cellular mechanisms of lung cancer progression and determine whether Talin-1 is a suppressor of metastasis in lung cancer. These studies will also lead to the development of new prognostic indicators and therapeutic strategies for treatment of metastatic lung cancer.