Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer.

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.

Nature communications. 2021 Feb 01*** epublish ***

Jeremy J McGuire, Jeremy S Frieling, Chen Hao Lo, Tao Li, Ayaz Muhammad, Harshani R Lawrence, Nicholas J Lawrence, Leah M Cook, Conor C Lynch

Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA., Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA., Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. .