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

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

doi:10.1038/s41467-021-20962-6

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.

Highlights

Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts
We found that chronic exposure to MSCs leads to the selection of PCa populations that display a shift to IL28Rα-STAT3 signaling and that are resistant to IL-28 induced apoptosis, and to conventional chemotherapies such as etoposide and docetaxel
Human and mouse bone metastatic prostate cancer specimens were initially assessed for MSC content by immunohistochemistry (IHC)

Summary

Introduction

Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. Chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL28-induced apoptosis and therapeutics such as docetaxel. STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. We report that bone-marrow derived MSCs produce IL28 and that this provokes rapid apoptosis of bone metastatic prostate cancer cells via IL-28Rα-STAT1 signaling, which has known roles in apoptosis, and in anti-viral and immune responses[18]. STAT3 is generally considered to be protumorigenic[19,20] and is hyperactivated in bone metastatic prostate cancer[21,22] In accord with these findings, treatment of MSCselected PCa cells with a selective small molecule inhibitor of STAT3, S3I-201, impaired their growth and survival ex vivo and in vivo. The IL-28Rα-STAT3 signaling circuit represents an attractive and therapeutically tractable vulnerability for bone metastatic prostate cancer

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