Novel Mechanisms of Carcinoma Cell Migration

大多数乳腺癌死亡直接是由于肿瘤通过侵袭和转移而扩散。 转移细胞运动性是肿瘤细胞侵袭和转移的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极好靶点，具有潜在的 降低乳腺癌患者的发病率和死亡率。为了更好地理解运动，我们研究整合素， 其是细胞外基质的受体，其传递对细胞运动至关重要的信号。 最近，整合素已被证明可以调节蛋白激酶A（PKA）。重要的是，这一规定 由于PKA参与Rac和Rho GTP酶的控制，PKA对细胞运动性至关重要。 然而，整合素调节PKA的机制以及PKA如何调节Rac和Rho是未知的。 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 促进癌细胞侵袭，使得PKA活性可被适当地靶向用于治疗干预。 本研究的目的是了解PI整合素对PKA活性的调节如何控制Rac和 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π 整合素调节PKA。我们接下来的两个目标是阐明PKA活性 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 与乳腺癌细胞运动性和扩散相关，使用手术样本，体外运动性和 侵袭测定和动物模型。通过该提案的结果，我们希望描绘出信号 PKA上游和下游的分子，这些分子是细胞迁移所必需的， 靶向PKA用于晚期癌症治疗性干预。

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.