TY - JOUR
T1 - 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.
N1 - Funding Information:
This work was supported by a Department of Defense Prostate Cancer Research Program (DOD PCRP) award (CCL: W81XWH1810523) and a Miles for Moffitt Foundation Award. This work was also supported in part by the Core Facilities of the Moffitt Cancer Center Grant P30-CA076292 and by R50CA211447 (HRL). We thank the patients, families, and dedicated researchers; Celestia Higano, Pete Nelson, Evan Yu, Elahe Mostaghel, Bruce Montgomery, Paul Lange, Xiaotun Zhang, Martine Roudier, Lawrence True, Robert Vessella, Eva Corey, Colm Morrissey and the rapid autopsy teams for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Program; supported by the Pacific Northwest Prostate Cancer SPORE (P50CA97186). The authors would also like to thank Drs. John Cleveland and Srikumar Chellappan for critical review of this study.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85100276624&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100276624&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-20962-6
DO - 10.1038/s41467-021-20962-6
M3 - Article
C2 - 33526787
AN - SCOPUS:85100276624
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 723
ER -