Spatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones

Journal article

The molecular mechanisms underlying lethal castration-resistant prostate cancer remain poorly understood, with intratumoral heterogeneity a likely contributing factor. To examine the temporal aspects of resistance, we analyze tumor heterogeneity in needle biopsies collected before and after treatment with androgen deprivation therapy. By doing so, we are able to couple clinical responsiveness and morphological information such as Gleason score to transcriptome-wide data. Our data-driven analysis of transcriptomes identifies several distinct intratumoral cell populations, characterized by their unique gene expression profiles. Certain cell populations present before treatment exhibit gene expression profiles that match those of resistant tumor cell clusters, present after treatment. We confirm that these clusters are resistant by the localization of active androgen receptors to the nuclei in cancer cells post-treatment. Our data also demonstrates that most stromal cells adjacent to resistant clusters do not express the androgen receptor, and we identify differentially expressed genes for these cells. Altogether, this study shows the potential to increase the power in predicting resistant tumors

Authors: Marklund, M; Schultz, N; Friedrich, S; Berglund, E; Tarish, F

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 13
• Issue: 1
• Pages: 5475-5475
• Article number: 5475
• Publication date: 2022-09-17
• DOI: 10.1038/s41467-022-33069-3
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Androgen deprivation therapy; Computational biology; Endocrinology; Biology; Gene expression; Cell; Cancer research; Hormone; Prostate; Prostate cancer; Downregulation and upregulation; Genetics; Transcriptome; Androgen receptor; Cancer; Androgen; Gene; Gene expression profiling; Stromal cell