PI3K Beta regulation of tumor metastasis

为了提高乳腺癌的治疗水平，了解乳腺癌转移的机制是至关重要的。 重要的是，乳腺癌的转移是由肿瘤和肿瘤之间的旁分泌和旁分泌信号驱动的。 间质细胞，如巨噬细胞和血小板。在原发肿瘤中，巨噬细胞增强肿瘤细胞 在肺中，巨噬细胞促进肿瘤细胞的外渗、存活和 成长。血小板也在肿瘤转移中起主要作用，因为血小板保护循环中的肿瘤细胞不受 免疫监视，诱导肿瘤细胞EMT，并将中性粒细胞招募到转移部位。血小板也 增强肿瘤细胞在远端部位的黏附和渗出。 这一建议检验了I类PI3K，PI3Kβ是转移的关键调节因子的假设。有选择性的 PI3KPTEN的抑制剂是可用的，但临床试验主要集中在β缺失肿瘤的生长和 没有直接解决转移问题。我们发表的数据表明，肿瘤细胞中的PI3Kβ需要 侵袭和实验性转移。新的初步数据显示，巨噬细胞和血小板 表达突变的PI3Kβ在激发肿瘤细胞的多种促转移反应方面存在缺陷。 重要的是，我们还表明，药物抑制小鼠的PI3Kβ导致显著减少 体内肿瘤细胞渗出。 该项目将直接测试PI3Kβ在转移中的作用。目的1研究PI3Kβ在旁曲林中的作用 以及肿瘤细胞和巨噬细胞之间的旁分泌信号，使用体外共培养实验，在体内 肿瘤研究和活体成像。目的2研究PI3Kβ在血小板-肿瘤相互作用中的作用 论血小板对肿瘤细胞信号和干细胞的调节作用。目标3将研究PI3Kβ在 体内自发转移。我们将在肿瘤细胞中表达突变的PI3Kβ，在间质细胞中表达，并 选择性地存在于巨噬细胞和血小板中。这些研究将使用活体成像和一种新的肺窗 由核心A支持，以定义肿瘤细胞、巨噬细胞和血小板在治疗期间和治疗后的行为 渗出。总之，这些研究将促进我们对PI3Kβ在肿瘤转移中的作用的理解。 并为使用PI3Kβ抑制剂治疗转移性疾病提供了重要的临床前数据。

To improve treatments for breast cancer, it is critical to understand the mechanisms mediating metastasis. Importantly, breast cancer metastasis is driven by paracrine and juxtacrine signaling between tumor and stromal cells, such as macrophages and platelets. In the primary tumor, macrophages enhance tumor cell invasion and intravasation, and in the lung, macrophages enhance tumor cell extravasation, survival and growth. Platelets also play a major role in tumor metastasis, as platelets protect circulating tumor cells from immune surveillance, induce tumor cell EMT, and recruit neutrophils to the metastatic site. Platelets also enhance tumor cell adhesion and extravasation at distal sites. This proposal examines the hypothesis that the Class I PI3K, PI3Kβ, is a key regulator of metastasis. Selective inhibitors of PI3Kβ are available, but clinical trials have largely focused on the growth of PTEN-null tumors and have not directly addressed metastasis. Our published data show that PI3Kβ in tumor cells is required for invasion and experimental metastasis. New preliminary data in this grant show that macrophages and platelets expressing mutant PI3Kβ are defective for stimulating a variety of pro-metastatic responses in tumor cells. Importantly, we also show that pharmacological inhibition of PI3Kβ in mice causes a dramatic reduction in tumor cell extravasation in vivo. This project will directly test the role of PI3Kβ in metastasis. Aim 1 examines the role of PI3Kβ in juxtracrine and paracrine signaling between tumor cells and macrophages, using in vitro co-culture experiments, in vivo tumor studies, and intravital imaging. Aim 2 examines the role of PI3Kβ in platelet-tumor interactions, focusing on platelet modulation of tumor cell signaling and stemness. Aim 3 will study the role of PI3Kβ during spontaneous metastasis in vivo. We will express mutant PI3Kβ in tumor cells, globally in stromal cells, and selectively in macrophages and platelets. These studies will use intravital imaging and a novel lung window supported by Core A to define the behavior of tumor cells, macrophages and platelets during and after extravasation. Together, these studies will advance our understanding of the role of PI3Kβ in tumor metastasis, and provide important preclinical data supporting the use of PI3Kβ inhibitors for metastatic disease.