Abstract IA08: Prostate cancer tumor dormancy and the development of metastases

Abstract

Abstract Cancer dormancy refers to the prolonged clinical disease-free time between removal of the primary tumor and recurrence, which is common in prostate cancer (PCa). PCa disseminated tumor cells (DTC) can be detected in the bone marrow of patients with no evidence of disease (NED) and advanced disease (ADV). However, the molecular and cellular nature of DTC is unknown. Single cell transcriptomic analyses comparing DTC in NED versus ADV PCa patients identified a molecular signature associated with the p38 stress activated kinase pathway and dormancy. Understanding the mechanism by which dormant tumor cells are triggered to proliferate may provide new targets for therapy. We have demonstrated that LuCaP PCa xenografts, which appear dormant in vitro, can be induced to proliferate through contact with each other and bone marrow stroma. Constitutive activation of myosin light chain kinase (MLCK), a downstream effector of integrin-β1 and TGFβ2, in non-proliferating cells promoted cell proliferation. Additionally, gene expression analyses and in vitro data support a role for TGFβ2 in suppressing proliferation. Taken together, these data point to a potential mechanism by which PCa cells are released from dormancy to form lethal metastases. The early dissemination of cells from the primary to other sites most likely involves epithelial-mesenchymal transition (EMT)-like behavior. It has been proposed that further dissemination can occur where a metastasis can seed further metastases. TGFβ is a known driver of EMT which is associated with tumor aggressiveness and metastasis. We assessed the natural history of tumor dissemination and EMT-related markers TGFβ, Twist, Slug, and Zeb1 in bone and visceral metastases from castration resistant PCa (CRPC) patients. Importantly, nuclear Twist, Slug, and Zeb1 were only present in a subset of epithelial cells that had an EMT-like phenotype, suggesting only a subset of cells display an EMT-like behavior in any given CRPC metastasis. These studies highlight the biological relevance of dormancy, cell-contact and EMT-like behavior in the seeding and establishment of CRPC metastases. Citation Format: Colm Morrissey. Prostate cancer tumor dormancy and the development of metastases. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA08.