Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling Journal Article
| Authors: | Chan, J. M.; Zaidi, S.; Love, J. R.; Zhao, J. L.; Setty, M.; Wadosky, K. M.; Gopalan, A.; Choo, Z. N.; Persad, S.; Choi, J.; LaClair, J.; Lawrence, K. E.; Chaudhary, O.; Xu, T.; Masilionis, I.; Linkov, I.; Wang, S.; Lee, C.; Barlas, A.; Morris, M. J.; Mazutis, L.; Chaligne, R.; Chen, Y.; Goodrich, D. W.; Karthaus, W. R.; Pe'er, D.; Sawyers, C. L. |
| Article Title: | 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 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. © 2022 American Association for the Advancement of Science. All rights reserved. |
| Keywords: | signal transduction; genetics; mouse; animal; metabolism; animals; mice; protein kinase inhibitor; protein kinase inhibitors; prostatic neoplasms; janus kinase; prostate tumor; androgen antagonists; antiandrogen; stat protein; janus kinases; stat transcription factors; humans; human; male |
| Journal Title: | Science |
| Volume: | 377 |
| Issue: | 6611 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2022-09-09 |
| Start Page: | 1180 |
| End Page: | 1191 |
| Language: | English |
| DOI: | 10.1126/science.abn0478 |
| PUBMED: | 35981096 |
| PROVIDER: | scopus |
| PMCID: | PMC9653178 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 October 2022 -- Source: Scopus |
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