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

Jeremy J. McGuire, Jeremy S. Frieling, Chen Hao Lo, Tao Li, Ayaz Muhammad, Harshani R. Lawrence, Nicholas J. Lawrence, Leah M. Cook and Conor C. Lynch ()
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Jeremy J. McGuire: University of South Florida
Jeremy S. Frieling: H. Lee Moffitt Cancer Center and Research Institute
Chen Hao Lo: University of South Florida
Tao Li: H. Lee Moffitt Cancer Center and Research Institute
Ayaz Muhammad: H. Lee Moffitt Cancer Center and Research Institute
Harshani R. Lawrence: H. Lee Moffitt Cancer Center and Research Institute
Nicholas J. Lawrence: H. Lee Moffitt Cancer Center and Research Institute
Leah M. Cook: University of Nebraska Medical Center
Conor C. Lynch: H. Lee Moffitt Cancer Center and Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-20962-6

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