Novel Mechanisms of Carcinoma Cell Migration

描述(申请人提供)：大多数乳腺癌死亡直接由肿瘤通过侵袭和转移传播所致。细胞运动是肿瘤细胞侵袭和转移的一个基本且不可或缺的方面。因此，细胞运动是治疗干预的一个极好的靶点，有可能降低乳腺癌患者的发病率和死亡率。为了更好地了解运动性，我们研究了整合素，它是细胞外基质的受体，传递对细胞运动性至关重要的信号。近年来，整合素被证明对蛋白激酶A(PKA)具有调节作用。重要的是，由于PKA参与了RAC和Rho GTP酶的控制，所以这种对PKA的调节对细胞运动至关重要。然而，PKA整合素调控机制以及PKA如何调控Rac和Rho尚不清楚。该项目的长期目标是了解整合素及其对PKA活性的调控如何促进癌细胞的侵袭，以便适当地针对PKA活性进行治疗干预。这项建议的目的是了解pi整合素对PKA活性的调节如何在癌细胞的趋化迁移中控制Rac和Rho小GTP酶。我们的第一个目标是确定pi整合素如何调控PKA。我们接下来的两个目标是为了阐明PKA活性调节RhoA和racl活性的机制。在我们的第四个目标中，我们将使用手术样本、体外运动和侵袭分析和动物模型来确定哪些PKA亚基与乳腺癌细胞的运动和扩散有关。根据这一建议的结果，我们希望描绘出细胞迁移所需的PKA上游和下游的信号分子，以便我们能够智能地针对PKA进行晚期癌症的治疗干预。

DESCRIPTION (provided by applicant): The majority of breast cancer deaths are directly due to tumor dissemination through invasion and metastasis. Cell motility is a fundamental and indispensable aspect of both tumor cell invasion and metastasis. As such, cell motility is an excellent target for therapeutic intervention with the potential to decrease breast cancer patient morbidity and mortality. To better understand motility, we study integrins, which are receptors for the extracellular matrix that transduce signals that are critical for cell motility. Recently, integrins have been shown to regulate Protein Kinase A (PKA). Importantly, this regulation of PKA is critical for cell motility due to the involvement of PKA in the control of Rac and Rho GTPases. However, the mechanisms governing integrin regulation of PKA and how PKA regulates Rac and Rho are unclear. The long-term goal of this project is to understand how integrins and their control of PKA activity promote carcinoma cell invasion so that PKA activity may be properly targeted for therapeutic intervention. The objective of this proposal is to understand how pi integrin regulation of PKA activity controls Rac and Rho small GTPases in the chemotactic migration of carcinoma cells. Our first aim is to determine how pi integrins regulate PKA. Our next two aims are designed to elucidate the mechanisms by which PKA activity regulates the activities of RhoA and Racl. In our fourth aim, we will identify which PKA subunits are associated with breast cancer cell motility and dissemination using surgical samples, in vitro motility and invasion assays and animal models. With the results from this proposal, we expect to delineate the signaling molecules upstream and downstream of PKA that are required for cell migration so that we can intelligently target PKA for therapeutic intervention of late stage cancer.