Distinct mesenchymal cell states mediate prostate cancer progression.

TitleDistinct mesenchymal cell states mediate prostate cancer progression.
Publication TypeJournal Article
Year of Publication2023
AuthorsPakula H, Omar M, Carelli R, Pederzoli F, Fanelli GNicolò, Pannellini T, Van Emmenis L, Rodrigues S, Fidalgo-Ribeiro C, Nuzzo PV, Brady NJ, Jere M, Unkenholz C, Alexanderani MK, Khani F, de Almeida FNunes, Abate-Shen C, Greenblatt MB, Rickman DS, Barbieri CE, Robinson BD, Marchionni L, Loda M
Date Published2023 Apr 01

Alterations in tumor stroma influence prostate cancer progression and metastatic potential. However, the molecular underpinnings of this stromal-epithelial crosstalk are largely unknown. Here, we compare mesenchymal cells from four genetically engineered mouse models (GEMMs) of prostate cancer representing different stages of the disease to their wild-type (WT) counterparts by single-cell RNA sequencing (scRNA-seq) and, ultimately, to human tumors with comparable genotypes. We identified 8 transcriptionally and functionally distinct stromal populations responsible for common and GEMM-specific transcriptional programs. We show that stromal responses are conserved in mouse models and human prostate cancers with the same genomic alterations. We noted striking similarities between the transcriptional profiles of the stroma of murine models of advanced disease and those of of human prostate cancer bone metastases. These profiles were then used to build a robust gene signature that can predict metastatic progression in prostate cancer patients with localized disease and is also associated with progression-free survival independent of Gleason score. Taken together, this offers new evidence that stromal microenvironment mediates prostate cancer progression, further identifying tissue-based biomarkers and potential therapeutic targets of aggressive and metastatic disease.

Alternate JournalbioRxiv
PubMed ID37034687
PubMed Central IDPMC10081210
Grant ListR01 CA173481 / CA / NCI NIH HHS / United States
R01 CA200859 / CA / NCI NIH HHS / United States
T32 CA260293 / CA / NCI NIH HHS / United States
P01 CA265768 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States
R01 CA183929 / CA / NCI NIH HHS / United States
Related Faculty: 
Nicholas Brady, Ph.D. Francesca Khani, M.D. Massimo Loda, M.D. Luigi Marchionni, M.D., Ph.D. Brian Robinson, M.D. Matthew B. Greenblatt, M.D., Ph.D. Pier Nuzzo, Ph.D. Mohamed Omar, MB, BCh

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700