Prostate cancer cells' IL-30 reprograms stromal fibroblasts via `IL6Rα/gp130` signaling, driving metastasis.

Prostate cancer (PC) progression and mortality are frequently driven by therapeutic resistance, often linked to dynamic tumor-stroma interactions. A significant challenge is the development of castration-resistant prostate cancer (CRPC), including aggressive double-negative CRPC (DNPC), which lacks conventional therapeutic targets. The molecular basis of cancer-fibroblast crosstalk, particularly the contribution of Interleukin (IL)-30, an emerging regulator of PC aggressiveness, remains incompletely understood. Elucidating this crosstalk is crucial for identifying novel therapeutic targets beyond current standard-of-care limitations.

Researchers investigated the role of IL-30 produced by prostate cancer (PC) cells in reprogramming stromal fibroblasts. They utilized in vitro co-culture models and a sophisticated two-organ-on-chip platform that linked PC-fibroblast spheroids to a bone marrow-like niche. The study examined fibroblast proliferation and differentiation, cancer cell migration, and colonization of the bone marrow microenvironment. Key methods included assessing gene expression via qPCR, analyzing signaling pathways like AKT and TGF-β/BMP, and evaluating the impact of IL-30 overexpression versus genetic depletion on these processes.

IL-30 produced by PC cells effectively reprogrammed stromal fibroblasts through IL6Rα/gp130 signaling, activating both AKT and TGF-β/BMP pathways. This reprogramming drove fibroblast proliferation and differentiation into pro-angiogenic cancer-associated fibroblasts (CAFs). Reciprocally, these CAFs amplified IL-30-mediated tumor aggressiveness by enhancing oncogenic transcriptional programs and promoting cancer cell migration. While fibroblast co-culture generally suppressed epithelial-mesenchymal transition (EMT)-associated genes like NOTCH1, SNAI1/2, and ZEB1 in PC cells, IL-30 overexpression overrode this suppression. It induced EMT regulators alongside key PC-associated genes such as IL6, LGALS4, HAL, and SHBG, whose expression correlated with IL-30 levels in clinical bone metastasis datasets. Using the organ-on-chip platform, fibroblasts significantly enhanced PC cell migration and colonization of the bone marrow microenvironment. > These pro-metastatic effects were potentiated by IL-30 overexpression and largely abrogated by its genetic depletion, highlighting a critical role for IL-30 in metastatic progression.