Defining and Characterizing Drivers of Lethal Metastatic Prostate Cancer

Project Summary: "Defining and Characterizing Drivers of Lethal Metastatic Prostate Cancer" Prostate cancer (PC) is the second leading cause of cancer-related deaths in the USA. PC is a slow growing disease, curable if detected early. However, the treatment resistant lethal form of PC is fast growing and metastatic. The goal of our proposed research is to identify genetic factors that are essential for the switch from indolent to lethal metastatic PC. We have generated a unique collection of a) PC patient derived organoids and b) primary cell lines from the 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 Axl is key to 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, we now focus on the receptor tyrosine kinase Axl and its control of the switch from primary to metastatic disease in vivo. In this proposal we will mechanistically validate the role of Axl receptor in PC cellular lineage reprogramming and maintenance of pro-metastatic phenotype (Aim 1). Next, we will assess the effect of androgen deprivation therapy (ADT) on a relevant mouse model of Axl-deficient PC and perform transcriptomic profiling to identify molecular changes occurring under the stress of ADT (Aim 2). To develop therapeutic strategies we will use a phosphoproteome approach and identify targetable kinase dependencies in these Axl-deficient metastatic cells (Aim 3). To execute the proposed aims, we will closely collaborate with experts in receptor signaling and PC 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.