Abstract 1343: Mesenchymal cell populations associated with different stages of prostate cancer progression in mice and human
Authors: Omar Mohamed , Pakula Hubert , Pederzoli Filippo , Fanelli Giuseppe N. , Panellinni Tania , Carelli Ryan , Rodrigues Silvia , Fidalgo-Ribeiro Caroline , Nuzzo Pier V. , Emmenis Lucie V. , Mohammad Mohammad , Jere Madhavi , Unkenholz Caitlin , Rickman David , Barbieri Christopher , Robinson Brian , Marchionni Luigi , Loda Massimo 
Published: April 2023

Abstract
Mesenchymal cells in the prostate cancer (PCa) tumor microenvironment (TME) contribute to the biological and clinical history of PCa. Indeed, mesenchymal cells heavily interact with cancer cells, immune cells, and the other cellular and non-cellular components of the TME to favor or hinder carcinogenesis and tumor progression. Using a comprehensive array of genetically engineered mouse models (GEMMs) of prostate cancer, 8 mesenchymal populations with different transcriptional programs are preferentially enriched in specific GEMMs at different stages of PCa. Here, we determine the transferability of this mesenchymal cluster designation from mice PCa models to human PCa cases. To this end, we compared: a) Tmprss2-ERG (T-ERG) mouse and ERG+ human cases; b) Pb4-Cre+/-;Ptenf/f;LSL-MYCN+/+;Rb1f/f (PRN) mouse and PCa bone metastasis. We generated scRNA-seq data for &gt; 8000 mesenchymal cells from ERG+ (n=6) and ERG- (n=3) PCa patients, and we retrieved data for bone metastasis mesenchymal cells (osteoblasts, osteoclasts, endothelial cells, pericytes; 1,872 total cells) from GSE143791. To transfer the stromal mouse clusters’ labels to human data, human gene symbols were converted to their mouse counterparts, then both datasets were restricted to overlapping genes. For the human PCa cases, label transfer was performed through ‘ingest’ using the scRNA-seq data from the mouse T-ERG model as reference for the human ERG+ cases and data from the remaining GEMMs as reference for the human ERG- cases. For bone metastases cases, mouse stromal data from all GEMMs were used to project the 8 stromal clusters to the mesenchymal cells in the bone metastases microenvironment. Not surprisingly, ERG+ human samples were enriched (&gt; 60% of total stromal cells) in mouse stroma clusters predominantly present in T-ERG mouse model, characterized by the expression of Wnt regulators and AR. Common populations to all murine models, representing myofibroblasts and immunomodulatory fibroblasts (expressing Gpx3, C3, C7, Cfh), were also commonly present in patients, irrespectively to the ERG status. In the PCa bone metastases, mesenchymal clusters enriched in the PRN model were strongly represented in human bone metastases, comprising &gt; 60% of total stromal cells. These cells were characterized by high expression of POSTN and MKI67, as well as bone-specific genes like BGN. Altogether, these findings suggest that our mesenchymal cluster designation developed using GEMMs can be meaningfully applied to human PCa, and that the different transcriptional programs we identified in distinct mesenchymal population are conserved across species. This lays the foundation for the utilization of defined genetically-engineered models in defining the interactions and cross-talks between different mesenchymal populations in relation to cancer and immune cells and other components of the TME in human prostate cancer.
Citation Format: Mohamed Omar, Hubert Pakula, Filippo Pederzoli, Giuseppe N. Fanelli, Tania Panellinni, Ryan Carelli, Silvia Rodrigues, Caroline Fidalgo-Ribeiro, Pier V. Nuzzo, Lucie V. Emmenis, Mohammad Mohammad, Madhavi Jere, Caitlin Unkenholz, David Rickman, Christopher Barbieri, Brian Robinson, Luigi Marchionni, Massimo Loda. Mesenchymal cell populations associated with different stages of prostate cancer progression in mice and human [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 1343.