Abstract 2757: Investigating regulatory drivers of prostate cancer metastasis in circulating tumor cells

Abstract Prostate cancer is the most common cancer in men and the second-leading cause of death. Most prostate cancer deaths are due to metastasis, particularly to the bone. Metastasis occurs when cells from the primary tumor travel through the blood as circulating tumor cells (CTCs) and settle in metastatic sites. CTCs are difficult to collect from patients, and understanding the relationships between CTCs and the tumor phenotypes of origin could reveal mechanisms of cancer metastasis. Hence, we utilized several genetically engineered mouse models (GEMMs) of metastatic prostate cancer to evaluate tumor phenotypes and CTCs. We compared the tumor phenotypes of several GEMMs of metastatic prostate cancer and identified a level of heterogeneity among tumors, particularly focusing on a GEMM that demonstrated severe metastasis, especially to the bone. Next, we analyzed CTCs from this GEMM and focused our analysis on transcriptional states that are regulated by proteins called master regulators (MRs). MRs control the expression of groups of genes called regulons, and pharmacologically inhibiting these MRs may lead to reversal of cancer phenotypes. We hypothesized that these MRs may be mechanistic drivers of CTC cell state in prostate cancer metastasis. We investigated MRs enriched in CTCs from mice and screened and validated Lap2, the lamina-associated polypeptide 2 protein, as a regulatory driver in mice with metastatic prostate cancer. Analysis of bulk RNA-seq profiles from primary and metastatic prostate samples in The Cancer Genome Atlas and Stand Up to Cancer cohorts, respectively, revealed that the regulon-based activity of Lap2 was significantly higher in the latter group. Moreover, analysis of single-cell RNA-seq profiles of CTCs isolated from prostate cancer patients confirmed aberrant Lap2 activity. Finally, the role of Lap2 was assessed in human tissue from an engineered multi-organ-on-a-chip model of metastasis. Silencing of Lap2 production in cells dissociated from mouse CTC-derived organoids inhibited extravasation to the bone in the model, suggesting a critical role for Lap2 in metastasis. Our findings illustrate the unique transcriptional profile of prostate cancer CTCs associated with their metastatic potential. We identified Lap2 as a novel driver of CTC dissemination and metastasis in mice and validated its activity in human prostate cancer, which can aid future therapies to prevent metastatic progression in patients. Citation Format: Aunika Zheng, Aleksandar Obradovic, Kacey Ronaldson-Bouchard, Gordana Vunjak-Novakovic, Andrea Califano, Peter A. Sims, Cory Abate-Shen, Arianna Giacobbe. Investigating regulatory drivers of prostate cancer metastasis in circulating tumor cells 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 2757.