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Lookup NU author(s): Dr Pasquale RescignoORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2024 The Author(s). Although hypercoagulability is commonly associated with malignancies, whether coagulation factors directly affect tumor cell proliferation remains unclear. Herein, by performing single-cell RNA sequencing (scRNA-seq) of the prostate tumor microenvironment (TME) of mouse models of castration-resistant prostate cancer (CRPC), we report that immunosuppressive neutrophils (PMN-MDSCs) are a key extra-hepatic source of coagulation factor X (FX). FX activation within the TME enhances androgen-independent tumor growth by activating the protease-activated receptor 2 (PAR2) and the phosphorylation of ERK1/2 in tumor cells. Genetic and pharmacological inhibition of factor Xa (FXa) antagonizes the oncogenic activity of PMN-MDSCs, reduces tumor progression, and synergizes with enzalutamide therapy. Intriguingly, F10high PMN-MDSCs express the surface marker CD84 and CD84 ligation enhances F10 expression. Elevated levels of FX, CD84, and PAR2 in prostate tumors associate with worse survival in CRPC patients. This study provides evidence that FXa directly promotes cancer and highlights additional targets for PMN-MDSCs for cancer therapies.
Author(s): Cali B, Troiani M, Bressan S, Attanasio G, Merler S, Moscarda V, Mosole S, Ricci E, Guo C, Yuan W, Gallagher L, Lundberg A, Bernett I, Figueiredo I, Arzola RA, Abreut EB, D'Ambrosio M, Bancaro N, Brina D, Zumerle S, Pasquini E, Maddalena M, Lai P, Colucci M, Pernigoni N, Rinaldi A, Minardi D, Morlacco A, Moro FD, Sabbadin M, Galuppini F, Fassan M, Ruschoff JH, Moch H, Rescigno P, Francini E, Saieva C, Modesti M, Theurillat J-P, Gillessen S, Wilgenbus P, Graf C, Ruf W, De Bono J, Alimonti A
Publication type: Article
Publication status: Published
Journal: Cancer Cell
Year: 2024
Volume: 42
Issue: 10
Pages: 1676-1692.e11
Print publication date: 14/10/2024
Online publication date: 19/09/2024
Acceptance date: 22/08/2024
Date deposited: 07/11/2024
ISSN (print): 1535-6108
ISSN (electronic): 1878-3686
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ccell.2024.08.018
DOI: 10.1016/j.ccell.2024.08.018
Data Access Statement: Single-cell RNA-seq and RNA-seq data generated for this study have been deposited at GEO and are publicly available. GEO accession numbers are listed in the key resources table. The accession numbers for the other existing, publicly available, scRNA-seq and RNA-seq datasets analyzed for this study are listed in the key resources table.
PubMed id: 39303726
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