Spatio-temporal analysis of prostate tumors in situ suggests the pre-existence of ADT-resistance

The molecular mechanisms by which potentially lethal castration-resistant prostate cancer emerge in advanced metastatic prostate cancer are still poorly understood. Intratumor heterogeneity is believed to contribute to the fact that a majority of affected men succumb to the disease within a few years. In this study, we will challenge the conventional notion that castration-resistant prostate cancer cells evolve as a consequence of treatment. To examine the temporal aspects of resistance, we analyze tumor heterogeneity in core needle biopsies collected pre-and post-treatment. 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 identified several distinct intratumoral cell populations, characterized by their unique gene expression profiles. Strikingly, certain minor cell populations present before treatment exhibited gene expression profiles that matched those of resistant tumor cell clusters. Such resistant clusters were confirmed by the localization of the androgen receptor to the nuclei in cancer cells present after treatment. Our data also demonstrate that stromal cells adjacent to resistant tumor factors do not express AR before treatment (or after), which can be used to increase the power in predicting resistant tumors.
QC 20200511