Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling

Abstract

Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on elevated JAK and FGFR activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice, by upregulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis 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.

Tumor-educated Gr1+CD11b+cells instigate breast cancer metastasis by twisting cancer cells plasticity via OSM/IL6–JAK signaling

“…As JAKs/STATS are activated by both IFN and OSM/IL6 receptors, it is conceivable that OSM/IL6 only activates a subset of the IFN-induced genes with tumor-promoting activity, as the case for Mx1 75 . Consistent with our findings, JAK/STAT signaling has recently been shown to initiate the lineage plasticity in prostate cancer as well as to promote lineage plasticity-driven targeted therapy resistance in a stem-like subpopulation of prostate cancer 76,77 . On the other hand, Aouad et al showed that epithelial-mesenchymal plasticity is essential for the generation of a dormant cell state of ER + breast cancer during progression, and the activation of IL6-JAK-STAT signaling triggers tumor cell awakening and recurrence 48 .…”

Non-Coding RNA Related to MAPK Signaling Pathway in Liver Cancer

“…The results revealed that the lineage plasticity in prostate cancer originates from epithelial cells as defined by a mixed lumen–basal phenotype. Furthermore, the JAK/STAT signaling pathway and FGFR are the main drivers of transforming prostate cancer into castration-tolerant or castration-resistant prostate cancer (CRPC) [ 131 ].…”

A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer

“…For example, the identification of histone deacetylases and other epigenetic modifying agents is consistent with the known importance of epigenetic regulation of androgen receptor signaling [60, 61]. Other targets, however, are linked to AR signaling bypass, as in the case of PTEN loss and subsequent constitutive activation of PI3K signaling [62], activation of JAK/STAT and FGFR signaling during the acquisition of AR independence and lineage plasticity [63, 64], and the role of Syk as a potential mediator of invasive features and bone metastasis [65]. While the relevance of these targets is well supported by preclinical evidence, the clinical utility of these targets is more varied.…”