Abstract B017: Multiomic single-cell profiling of a novel MYC-driven mouse prostate cancer model

Abstract MYC overexpression, often associated with chromosome 8q24 amplification, is a well identified genetic alteration in aggressive prostate cancer, especially in metastatic castration-resistant prostate cancer (mCRPC). It has been reported that MYC amplification counteracts with androgen receptor (AR) signaling, which has significant impacts on androgen deprivation therapy efficacy. In this study, we developed a prostate cancer mouse model in which MYC overexpression is initially induced by AR but AR-independent during tumorigenesis and progression. We employed the Multiome technology integrating single-cell RNA-sequencing (scRNA-seq) and ATAC-sequencing (scATAC-seq) to profile late-stage MYC-driven non-metastatic and metastatic prostate cancers. Consistent with previous studies using AR-dependent MYC-driven models, we identified that primary tumors are composed of a large quantity of luminal cells. We have also observed a higher proportion of luminal cells in the tumors that developed metastasis, while localized primary tumors were more abundant in basal cells, and transitional cell types. Interestingly, we uncovered heterogeneous transitional populations featured by different cell cycle profiles and cell-type gene signatures. With gene set enrichment analysis (GSEA), we identified differential enrichment of inflammatory pathways in luminal cells in metastatic primary tumors relative to localized primary tumors. By integrating with scATAC-seq analysis, we also identified new differential transcriptional and epigenetic regulators that may drive the aggressiveness of these MYC-driven cancers in a tissue specific manner. In addition, we applied inferred copy number variation (CNV) analysis and showed that aggressive tumors and metastasis harbor higher levels of CNVs. Together, these findings reveal how MYC overexpression reshapes prostate epithelial lineage, chromatin landscape and genomic instability to promote AR-independent aggressiveness, providing mechanistic insights and a foundation for future therapeutic targeting of MYC-driven malignancies. Citation Format: Kathryn Echandía-Monroe, Sofia Hu, Daniel R. Schmidt, Kun-Lin Ho, Duanduan Ma, Elise G. DeArment, Faith Kim, Chloe Springer, Savannah Washburn, Madeline M. Wong, Kate Lu, Marianna Trakala, William D. Figg, Matthew G. Vander Heiden, Xiaofeng A. Su. Multiomic single-cell profiling of a novel MYC-driven mouse prostate cancer model abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr B017.