LAUSR

Bone metastatic prostate cancer is painful and incurable. We believe that understanding the interactions of tumor cells and the surrounding stromal cells may provide new therapeutic options. Bone metastatic prostate cancer promotes mesenchymal stem cell (MSC) recruitment and differentiation into osteoblasts, leading to the clinically often-observed osteogenic phenotype. However, the reciprocal roles of bone- marrow derived MSCs on prostate cancer cells are less explored. Here, we discovered that MSCs significantly suppress prostate cancer growth in vitro and in vivo. Mechanistically, we show that MSC-derived interleukin-28 (IL-28) promotes prostate cancer cell apoptosis via the IL-28 receptor alpha (IL-28Rα). However, chronic exposure to MSCs yields prostate cancer cell populations that are resistant to IL-28 induced apoptosis and therapeutics such as docetaxel. In vivo, we observed that MSC selected prostate cancer cells rather than being suppressed, grow at a significantly enhanced rate in bone. The increase in apoptosis resistance is accompanied by a shift in downstream signaling of the IL-28Rα from STAT1 to STAT3. Reduction of STAT3 levels or pharmacological inhibition (STI-201) significantly reduces the growth of MSC selected prostate cancer cells in vitro and in vivo. Collectively, these data shed light on how MSCs in the bone marrow microenvironment initially protect against prostate cancer cell establishment but in doing so, help select for aggressive, apoptosis resistant bone metastatic prostate cancer cells that are more aggressive. Given that the majority of prostate to bone metastases are positive for STAT3 expression and activity, our data provide rationale for the therapeutic targeting of STAT3 in bone metastatic prostate cancer. Citation Format: Jeremy J. Mcguire, Leah Cook, Jeremy Frieling, Ayaz Muhammad, Harshani Lawrence, Nicholas Lawrence, Conor Lynch. Mesenchymal stem cell-derived interleukin-28 can drive the selection of apoptosis resistant bone metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1992.