TY - JOUR TI - Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer AU - McGuire, Jeremy J. AU - Frieling, Jeremy S. AU - Lo, Chen Hao AU - Li, Tao AU - Muhammad, Ayaz AU - Lawrence, Harshani R. AU - Lawrence, Nicholas J. AU - Cook, Leah M. AU - Lynch, Conor C. T2 - Nature Communications AB - Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3. DA - 2021/02/01/ PY - 2021 DO - 10.1038/s41467-021-20962-6 DP - www.nature.com VL - 12 IS - 1 SP - 723 LA - en SN - 2041-1723 UR - https://www.nature.com/articles/s41467-021-20962-6 Y2 - 2021/02/01/19:40:50 ER -