Novel Mechanisms of Carcinoma Cell Migration

描述（由申请人提供）：大多数乳腺癌死亡是由肿瘤通过侵袭和转移传播直接导致的。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。因此，细胞运动是治疗干预的一个极好的目标，具有降低乳腺癌患者发病率和死亡率的潜力。为了更好地理解运动，我们研究了整合素，它是细胞外基质的受体，传递对细胞运动至关重要的信号。近年来，整合素已被证实可调控蛋白激酶A （PKA）。重要的是，由于PKA参与Rac和Rho gtpase的控制，PKA的这种调节对细胞运动至关重要。然而，整合素调控PKA的机制以及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活性的控制如何促进癌细胞的侵袭，从而使PKA活性可以适当地靶向治疗干预。本研究的目的是了解pi整合素调控PKA活性如何控制Rac和Rho小gtpase在癌细胞趋化迁移中的作用。我们的第一个目标是确定π整合素如何调节PKA。我们接下来的两个目标是阐明PKA活性调节RhoA和Racl活性的机制。在我们的第四个目标中，我们将通过手术样本、体外运动和侵袭试验以及动物模型来确定哪些PKA亚基与乳腺癌细胞的运动和传播有关。根据这项研究的结果，我们希望能够描述PKA上游和下游的信号分子，这些信号分子是细胞迁移所必需的，这样我们就可以智能地靶向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.