GSE210358
Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling
In many cancers, treatment failure is linked to changes in tumor cell state or lineage, and often involves the reactivation of stem-like or developmental transcriptional programs. How this plasticity unfolds at a molecular level and whether it plays a causal role in drug resistance remains unclear. Here, we model the origin and dynamics of lineage plasticity in prostate cancer and its relationship to antiandrogen-based therapeutic resistance. In time course experiments utilizing genetically engineered mouse models and murine organoid cultures of prostate cancer, we find that plasticity initiates in an epithelial population defined by mixed luminal and basal lineage gene expression, and that it depends on elevated JAK and FGFR kinase activity. Organoid cultures from patients with late-stage castration-resistant disease harboring mixed-lineage cells reproduce the dependency we observe in mice, by upregulating luminal gene expression upon JAK and FGFR kinase inhibitor treatment. Single-cell analysis of human tumor samples confirms the presence of mixed lineage cells with elevated JAK/STAT and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials. Overall design: Here, we model the origin and dynamics of lineage plasticity in prostate cancer and its relationship to antiandrogen-based therapeutic resistance. In time course experiments utilizing genetically engineered mouse models and murine organoid cultures of prostate cancer.