Abstract 142: Candidate measures of lineage plasticity in aggressive phenotypes of prostate cancer

Abstract

Abstract Lineage plasticity in cancer reflects the property of neoplastic cells to adapt to external pressures by switching between different developmental pathways. While some prostate cancers appear “constrained” to a luminal epithelial lineage despite progression on androgen signaling inhibitors, others exhibit a “lineage-promiscuous” phenotype under the pressures of these therapies. However, a clinically applicable marker that quantifies lineage plasticity has yet to be developed. To address this knowledge gap, we applied single-cell genomics and bulk epigenetic profiling to two patient derived xenografts (PDXs) derived before and after chemotherapy from the castration-resistant prostate tumor of a 42-year-old with a PSA 486, Gleason 5+4, cT4N1M1b PCa, who succumbed to his disease within 21 months of diagnosis. We reasoned that the two PDXs, MDA PCa 177-B (AR negative, basal transcriptional profile) and MDA PCa 189-1 (AR positive, luminal transcriptional profile), should share the property of lineage plasticity and serve to define candidate measurable signatures of this property. Targeted and single-cell DNA sequencing showed that the two models share 66.8% of their annotated mutations, 71.5% of copy number variations, and a common ancestor in their phylogeny, confirming their common clonal origin. Single-cell RNA sequencing revealed the presence of a cluster of cells shared by both PDXs that contained a highly mixed program, similar to a “high-plasticity cell state” (HPCS) previously implicated in the emergence and maintenance of cellular heterogeneity in genetically engineered mouse models of lung cancer (Marjanovic et al PMID: 32707077). H3K27ac, H3K27me3 and H3K4me3 chromatin immunoprecipitation followed by sequencing and reduced representation bisulfite sequencing performed in triplicates revealed chromatin profiles shared by both PDX models, and being absent from normal prostate specimens in publicly available datasets. In conclusion, our data supports the hypothesis that the property of lineage plasticity can be reflected in a biomarker signature and used as a measurable metric. Ongoing are evaluation of the candidate signatures in publicly available datasets representative of the spectrum of the disease in patient samples, and assessment of the effects of systemic therapies (including epigenetic modulators) on the property of lineage plasticity in clinical and co-clinical samples. Citation Format: Souzana Logotheti, Haswanth Vundavilli, Eugenia Papadaki, Yuehui Zhao, Marcos Roberto Estecio, Rama Soundararajan, Peter Shepherd, Jiabin Dong, Anh Hoang, Shuai Guo, Nora Navone, Vasiliki Tzelepi, Christopher Logothetis, Yue Lu, Aristidis Vrahatis, Wenyi Wang, Ana Aparicio. Candidate measures of lineage plasticity in aggressive phenotypes of 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 142.