Abstract 2756: Single cell analysis reveals treatment response-associated plastic cell state and lineage switching in aggressive variant prostate cancer

Abstract Prostate cancer (PCa) is a common malignancy in men over 65, ranking as the second leading cause of cancer-related deaths among men in the United States. While most prostate cancers respond to androgen receptor (AR) targeting therapies, Aggressive Variant Prostate Cancers (AVPCs), characterized by RB1, Tp53, and/or PTEN alterations, do not. AVPCs exhibit lineage plasticity in preclinical models, enabling the expression of non-prostate epithelial lineage markers to adapt to therapeutic pressures. However, a measurable definition of lineage plasticity as a potential therapeutic target for clinical trials is currently lacking. To arrive at said definition, we perform single-nuclei RNA sequencing (snRNA-seq) on lymph node metastases from twelve AVPC patients with matched sample pairs of both pre- and post-treatment. Additionally, we include snRNA-seq data from eight non-AVPC patients as a baseline. Expanding upon our prior establishment of tumor-specific total mRNA expression (TmS) as an indicator of tumor cell lineage plasticity (Nature Biotechnology, PMID: 35697807), we employ unique molecular identifier (UMI) counts from individual cells to quantify this plasticity. We reveal a distinct cluster of tumor cells with notably high UMI counts in resistant samples, indicative of a less differentiated state and increased transcriptional diversity. This high-UMI cluster is marked by significant enrichment in pathways associated with epithelial-mesenchymal transition (EMT), stemness, one-carbon metabolism, and arginine metabolism pathways. Concurrently, there is a reduction in activity within the androgen receptor (AR) and DNA damage repair pathways. These characteristics suggest an enhanced capacity for lineage switching in AVPC tumor cells, potentially contributing to evasion from targeted therapies. Moreover, immune components within resistant samples consistently display lower UMI counts, indicating a diminished propensity for lineage plasticity. In conclusion, we present a better understanding of lineage switching in therapeutic resistance in AVPCs, paving the way for novel treatment strategies in PCa management. Citation Format: Shuai Guo, Elavarasan Subramani, Daniel E. Frigo, Patrick G. Pilié, Sangeeta Goswami, Rama Soundararajan, Ana Aparicio, Wenyi Wang. Single cell analysis reveals treatment response-associated plastic cell state and lineage switching in aggressive variant prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2756.