Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2021
- Source ID
- 10.1038/s41467-021-20962-6
Entities
People
- Ayaz Muhammad
- Chen-Hao Lo
- Conor C Lynch
- Harshani R. Lawrence
- Jeremy Frieling
- Jeremy J. Mcguire
- Leah M Cook
- Nicholas J. Lawrence
- Tao Li
Organizations
- United States Department of Defense