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

Science. 2022 Sep 9;377(6611):1180-1191. doi: 10.1126/science.abn0478. Epub 2022 Aug 18.


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 increased Janus kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice by up-regulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed-lineage cells with increased JAK/STAT (signal transducer and activator of transcription) and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.

MeSH terms

  • Androgen Antagonists
  • Animals
  • Cell Plasticity*
  • Drug Resistance, Neoplasm*
  • ErbB Receptors*
  • Humans
  • Janus Kinase Inhibitors / therapeutic use
  • Janus Kinases* / genetics
  • Janus Kinases* / metabolism
  • Male
  • Mice
  • Neoplasms, Experimental
  • Organoids
  • Prostatic Neoplasms* / drug therapy
  • Prostatic Neoplasms* / pathology
  • STAT Transcription Factors* / genetics
  • STAT Transcription Factors* / metabolism
  • Signal Transduction


  • Androgen Antagonists
  • Janus Kinase Inhibitors
  • STAT Transcription Factors
  • EGFR protein, mouse
  • ErbB Receptors
  • Janus Kinases