| First Author | Wang H | Year | 2023 |
| Journal | Cancer Cell | Volume | 41 |
| Issue | 7 | Pages | 1345-1362.e9 |
| PubMed ID | 37352863 | Mgi Jnum | J:357456 |
| Mgi Id | MGI:7511249 | Doi | 10.1016/j.ccell.2023.05.016 |
| Citation | Wang H, et al. (2023) Antiandrogen treatment induces stromal cell reprogramming to promote castration resistance in prostate cancer. Cancer Cell 41(7):1345-1362.e9 |
| abstractText | Lineage plasticity causes therapeutic resistance; however, it remains unclear how the fate conversion and phenotype switching of cancer-associated fibroblasts (CAFs) are implicated in disease relapse. Here, we show that androgen deprivation therapy (ADT)-induced SPP1(+) myofibroblastic CAFs (myCAFs) are critical stromal constituents that drive the development of castration-resistant prostate cancer (CRPC). Our results reveal that SPP1(+) myCAFs arise from the inflammatory CAFs in hormone-sensitive PCa; therefore, they represent two functional states of an otherwise ontogenically identical cell type. Antiandrogen treatment unleashes TGF-beta signaling, resulting in SOX4-SWI/SNF-dependent CAF phenotype switching. SPP1(+) myCAFs in turn render PCa refractory to ADT via an SPP1-ERK paracrine mechanism. Importantly, these sub-myCAFs are associated with inferior therapeutic outcomes, providing the rationale for inhibiting polarization or paracrine mechanisms to circumvent castration resistance. Collectively, our results highlight that therapy-induced phenotypic switching of CAFs is coupled with disease progression and that targeting this stromal component may restrain CRPC. |
