Study: Transcriptional mediators of treatment resistance in lethal prostate cancer 2170 cells

Summary: Smart-seq2 sequencing of cells from metastatic castration resistant prostate cancer (mCRPC) from 14 patients.

Publication: https://www.nature.com/articles/s41591-021-01244-6

DOI: 10.1038/s41591-021-01244-6

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 inhibitors. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 advanced prostate cancer patients, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively co-expressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and TGF-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6, and NR1D2. 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 mCRPC provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.

Correspondence: Eliezer M. Van Allen (Dana-Farber Cancer Institute)