Abstract 5644: Spatially resolved transcriptomics points to distinct malignant cell populations within primary and castration resistant prostate cancer

Abstract Background: Prostate cancer (PCa) is the second most common cancer in men. Despite its high prevalence, many patients carry an indolent form of the disease and are thus suspect to overtreatment. Conversely, some cases treated with androgen deprivation therapy can develop into castration resistant prostate cancer (CRPC), for which there is no curative treatment. Understanding why some tumors are more aggressive than others could lead to more accurate patient risk stratification. Here we characterize cancer and normal cell subpopulations within prostate tissue in their spatial context using a multimodal integrative approach. Methods: We performed spatially resolved transcriptomics (ST) on a set of primary tumor PCa, CRPC and benign prostatic hyperplasia (BPH) patient samples. In addition to ST, we produced RNA-seq, DNA-seq and assay for transposase accessible chromatin using sequencing (ATAC-seq) data, allowing for multiomic integration within and across sample categories. We performed extensive analysis of ST data, employing unsupervised clustering, spot expression signal deconvolution, differential gene expression analysis and copy number variation (CNV) inference. Main Results: The systematic analysis of spot expression profiles revealed a high degree of variation in nearby tissue regions, as we found up to three unique luminal cell populations inside a one millimeter radius in PCa. Similarly in locally recurrent CRPC, we identified cumulative CNVs in proximal luminal cell populations, with the inferred CNV profiles validated through DNA-seq. A set of marker genes was calculated for each unique cell population, with multiple PCa associated genes found to be differentially expressed. Although we observed significant variation in the luminal cell populations, the stromal gene expression was markedly similar across all samples. Conclusions: We discovered shared, similar and unique cell populations both within and across different PCa and CRPC sections. We observed various luminal cell populations with distinct gene expression profiles in samples from both progression stages. The close spatial proximity of these cell clusters suggests that ST can be used to discover and examine finely detailed populations in their original spatial environment. Citation Format: Antti Kiviaho, Heini M. Kallio, Sini K. Eerola, Elisa M. Vuorinen, Tomi Häkkinen, Sinja Taavitsainen, Ebrahim Afyounian, Teemu Tolonen, Juha Kesseli, Alfonso Urbanucci, Kirsi J. Rautajoki, Teuvo L. Tammela, Tapio Visakorpi, Matti Nykter. Spatially resolved transcriptomics points to distinct malignant cell populations within primary and castration resistant prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5644.