Abstract 53: Axl is sufficient but not necessary for disseminated prostate tumor cell dormancy

Abstract

Abstract Prostate cancer (PCa) remains the second most common cancer among men in the U.S., and kills nearly 30,000 men each year. While the majority of patients with localized disease are cured by surgery and/or radiation, 10-15% of these patients will develop metastasis most commonly in the bone marrow. The time from primary tumor removal to recurrence can range from years to decades, and constitutes a period of minimal residual disease in which cancer cells remain in the body but are clinically undetectable. These disseminated tumor cells (DTCs) are seeds for lethal bone metastases and are thought to maintain a long-term state of dormancy in the bone marrow. Very little is known about the mechanism(s) by which dormancy is regulated, but further investigation may lead to therapeutic strategies aimed at preventing recurrent metastasis altogether. In this effort, we have previously found the secreted bone marrow factor Gas6 and the expression of its receptor Axl to be associated with dormant bone marrow DTCs in xenograft mouse models. We hypothesize that bone marrow Gas6 signals through Axl to induce dormancy in prostate DTCs, and explored the functional consequences of altering Axl expression in these models. To determine if Axl is sufficient to induce dormancy, we overexpressed it in the Axl-negative human PCa C42B cell line and monitored tumor growth by BLI after intracardiac injection in NSG mice. By the time half of the control overexpression injected mice developed tumors, less than 10% of mice injected with Axl overexpression cells developed tumor signal. This delay in tumorigenesis indicates a prolonged period of dormancy that is mediated by Axl expression. To determine if Axl is necessary for dormancy, we knocked out Axl in the Axl-positive human PCa PC3 cells using CRISPR and monitored growth after intracardiac injection in the same manner as the overexpression cells. Knockout of Axl did not increase the time to tumor signal compared to control cells. Loss of Axl also did not decrease the fraction of EdU negative, non-proliferative cells present in the bone marrow at one week post-injection. These data indicate that Axl is likely not necessary for DTC dormancy. Altogether this study suggests that Axl overexpression is sufficient to induce dormancy, but endogenous Axl is not required for dormancy. This is further supported by negative immunohistochemical staining of Axl on cancer cells within growing primary and metastatic tumors from a PCa tissue microarray. Axl also correlated with decreased incidence of biochemical recurrence (Decipher GRID) and increased overall survival (TCGA). Ongoing work includes assessing the expression of Axl on patient CTCs and DTCs, and correlating it with proliferation status. Citation Format: Haley D. Axelrod, Kenneth C. Valkenburg, Jessica L. Hicks, Angelo M. DeMarzo, Kenneth J. Pienta. Axl is sufficient but not necessary for disseminated prostate tumor cell dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 53.