PI3K Beta regulation of tumor metastasis

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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.