The Prostate · 2025
Understanding Enzalutamide-Resistance Based on a Functional Single-Cell Approach.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Xue Changhui, Ko Hyun-Kyung, Shi Kasen, Pittsenbarger Janet, Vu Dao Lucien, Shi Kaiyo, Libmann Maximilian, Geng Hao, Qian David Z
Аннотация
BACKGROUND: Anti-androgen or castration therapies are the mainstay treatment for metastatic prostate cancers (PCa). Although effective at first, androgen-dependent PCa (ADPC) universally develops therapy resistance, thereby evolving into an incurable disease called castration-resistant PCa (CRPC). Currently, mechanisms underlying the emergence of CRPC from ADPC are largely unclear.
METHODS: We used single-cell RNA-sequencing (scRNA-Seq) to determine the transcription heterogeneity of a therapy-naïve ADPC cell line-LNCaP and how it responded to the anti-androgen drug, enzalutamide. Based on the results, we used single-cell/colony-based cloning to isolate a pre-enzalutamide cell subset, displaying low and/or no expression of androgen receptor (ARlow/-).
RESULTS: We found that most LNCaP cells expressed enzalutamide-target androgen receptor (AR+), while a small subpopulation (~10%) expressed low or no AR (ARlow/-). Gene set enrichment analysis (GSEA) revealed that AR+ and ARlow/- cells were enriched with significantly different gene expressions and signaling pathways. Unexpectedly, ARlow/- cells displayed robust transcriptional response, including upregulations of genes and pathways involved in clinical CRPC. Next, we isolated ARlow/- and AR+ cells from enzalutamide-naïve LNCaP cells and functionally confirmed the enzalutamide-resistant phenotype of ARlow/- cells in vitro and in xenograft models in vivo. Through xenograft-based single-nucleus RNA-Seq, we further found that the ARlow/- cells were selected, while the AR+ cells were de-selected in vivo by enzalutamide. Also, we found that the selection and expansion of ARlow/- clone were recapitulated in another enzalutamide-resistant cell model.
CONCLUSION: In summary, our single-cell-based sequencing and functional tests suggest a clonal selection and expansion model of enzalutamide resistance, in which the pretreatment AR-low subpopulation is selected and expanded to confer treatment resistance.
METHODS: We used single-cell RNA-sequencing (scRNA-Seq) to determine the transcription heterogeneity of a therapy-naïve ADPC cell line-LNCaP and how it responded to the anti-androgen drug, enzalutamide. Based on the results, we used single-cell/colony-based cloning to isolate a pre-enzalutamide cell subset, displaying low and/or no expression of androgen receptor (ARlow/-).
RESULTS: We found that most LNCaP cells expressed enzalutamide-target androgen receptor (AR+), while a small subpopulation (~10%) expressed low or no AR (ARlow/-). Gene set enrichment analysis (GSEA) revealed that AR+ and ARlow/- cells were enriched with significantly different gene expressions and signaling pathways. Unexpectedly, ARlow/- cells displayed robust transcriptional response, including upregulations of genes and pathways involved in clinical CRPC. Next, we isolated ARlow/- and AR+ cells from enzalutamide-naïve LNCaP cells and functionally confirmed the enzalutamide-resistant phenotype of ARlow/- cells in vitro and in xenograft models in vivo. Through xenograft-based single-nucleus RNA-Seq, we further found that the ARlow/- cells were selected, while the AR+ cells were de-selected in vivo by enzalutamide. Also, we found that the selection and expansion of ARlow/- clone were recapitulated in another enzalutamide-resistant cell model.
CONCLUSION: In summary, our single-cell-based sequencing and functional tests suggest a clonal selection and expansion model of enzalutamide resistance, in which the pretreatment AR-low subpopulation is selected and expanded to confer treatment resistance.