Novel Mechanisms of Carcinoma Cell Migration

大多数乳腺癌死亡是由于肿瘤通过侵袭和转移而直接造成的 转移。细胞运动是肿瘤细胞侵袭和转移的一个基本和不可缺少的方面 转移。因此，细胞运动性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。为了更好地理解运动性，我们研究整合素， 它们是细胞外基质的受体，传递对细胞运动至关重要的信号。 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，这一规定 由于PKA参与了RAC和Rho GTP酶的调控，因此PKA对细胞运动至关重要。 然而，PKA的整合素调控机制以及PKA如何调控Rac和Rho是 不清楚。这个项目的长期目标是了解整合素及其对PKA活性的控制 促进癌细胞侵袭，从而使PKA活性成为治疗干预的适当靶点。 这项建议的目的是了解pi整合素调控PKA活性如何控制RAC和RAC Rho小GTP酶在癌细胞趋化迁移中的作用我们的第一个目标是确定pi是如何 整合素调控PKA。我们接下来的两个目标是为了阐明PKA活动的机制 调节RhoA和Racl的活性。在我们的第四个目标中，我们将确定哪些PKA亚基是 与乳腺癌细胞在手术标本中的运动和扩散有关，体外运动和 入侵分析和动物模型。根据这项提案的结果，我们预计将描绘出信号 PKA上游和下游的分子是细胞迁移所必需的，这样我们就可以智能地 靶向PKA用于晚期癌症的治疗干预。

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 studyintegrins, 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 activitycontrols 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 whichPKA 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.