Abstract
Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell–intrinsic epithelial–mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4–6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.
Highlights
In post-enzalutamide cells from the same patient, we observed no evidence of a selective sweep driven by any dominant single androgen receptor (AR) isoform, and almost all post-treatment isoforms were detectable in some cells before enzalutamide
AR-45 and AR-V7 were coexpressed in significantly fewer cells than expected by chance, but we did not observe a replacement of AR-45-expressing cells by AR-V7-expressing cells in post-enzalutamide biopsies (Supplementary Fig. 2c)
AR-V7, AR-V8 and AR-V9 were detected even in normal prostate and in Metastatic castration-resistant prostate cancer (mCRPC), no AR isoform was significantly associated with duration on treatment (Extended Data Fig. 3a)
Summary
After normalizing the number of isoform-specific reads to AR read count (as opposed to total read count), we observed no significant differences between exposed and naive tumors (Extended Data Fig. 3c). These observations suggest that the increased abundance after enzalutamide exposure of many isoforms (including AR-V7) may largely be a consequence of increased total AR expression and that the relative abundances of the different isoforms may be largely unchanged. Intron 3 contains many of the terminal cryptic/alternative exons included in truncated isoforms, so we quantified the proportion of total AR coverage from intron 3 or from a larger interval that includes upstream exons (Fig. 1f)[2] Increases in these measures may suggest expression of a greater proportion of transcripts that encode ligand-independent proteins. Combined with the lack of systematic differences before and after therapy, our observations suggest that assessments of single AR variants may be insufficient for a causal understanding of a tumor’s sensitivity to androgen-targeting therapies even if their detection can serve as a proxy of total AR
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