Defining and Characterizing Drivers of Lethal Metastatic Prostate Cancer

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Prostate cancer (PC) is the second leading cause of cancer-related deaths in the USA. The goal of our proposed research is to identify genetic factors that are essential for the switch from indolent to lethal metastatic prostate cancer. We have generated primary cell lines from tumor and metastasis of the RapidCaP mouse model for lethal PC (PTEN and TP53 deficient). Our preliminary data highlights a fundamental shift in cellular phenotype and growth signaling associated with the transition to metastasis. Most importantly, the loss of TAM kinase receptor is key for this metastasis associated cellular reprogramming event. These discrete cellular states are associated with divergent signaling behavior, which enables or restricts the metastatic potential of cancer cells. Therefore, our focus is now on delineating the role of TAM kinases in PC metastasis and the signaling cascade controlling the switch from primary to distant metastatic disease in vivo. In this proposal we will mechanistically validate the role of TAM receptors in PC cellular lineage reprogramming and maintenance of pro-metastatic EMT-like phenotype (Aims 1 and 3). Next, we will assess the role of PI3K/mTOR signaling axis in TAM-deficient PC (Aim 2). To execute the proposed aims, we will closely collaborate with experts in receptor signaling and prostate cancer disease biology. Our background in mouse genetics, cell biology and translational oncology is well aligned with the expertise required to carry out the proposed work and unravel the genetic dependencies of lethal metastatic PC cells.