凝血因子 X 促进前列腺癌对雄激素剥夺疗法的抵抗。
Coagulation factor X promotes resistance to androgen-deprivation therapy in prostate cancer.
发表日期：2024 Oct 14
作者：
Bianca Calì, Martina Troiani, Silvia Bressan, Giuseppe Attanasio, Sara Merler, Viola Moscarda, Simone Mosole, Elena Ricci, Christina Guo, Wei Yuan, Lewis Gallagher, Arian Lundberg, Ilona Bernett, Ines Figueiredo, Rydell Alvarez Arzola, Ernesto Bermudez Abreut, Mariantonietta D'Ambrosio, Nicolò Bancaro, Daniela Brina, Sara Zumerle, Emiliano Pasquini, Martino Maddalena, Ping Lai, Manuel Colucci, Nicolò Pernigoni, Andrea Rinaldi, Davide Minardi, Alessandro Morlacco, Fabrizio Dal Moro, Marianna Sabbadin, Francesca Galuppini, Matteo Fassan, Jan Hendrik Rüschoff, Holger Moch, Pasquale Rescigno, Edoardo Francini, Calogero Saieva, Mikol Modesti, Jean-Philippe Theurillat, Silke Gillessen, Petra Wilgenbus, Claudine Graf, Wolfram Ruf, Johann de Bono, Andrea Alimonti
来源：
CANCER CELL
摘要：
尽管高凝状态通常与恶性肿瘤相关，但凝血因子是否直接影响肿瘤细胞增殖仍不清楚。在此，通过对去势抵抗性前列腺癌 (CRPC) 小鼠模型的前列腺肿瘤微环境 (TME) 进行单细胞 RNA 测序 (scRNA-seq)，我们发现免疫抑制性中性粒细胞 (PMN-MDSC) 是一种关键的额外功能。凝血因子 X (FX) 的肝脏来源。 TME 内的 FX 激活通过激活肿瘤细胞中的蛋白酶激活受体 2 (PAR2) 和 ERK1/2 磷酸化来增强雄激素依赖性肿瘤生长。 Xa 因子 (FXa) 的遗传和药理学抑制可拮抗 PMN-MDSC 的致癌活性，减少肿瘤进展，并与恩杂鲁胺治疗产生协同作用。有趣的是，F10high PMN-MDSC 表达表面标记 CD84，并且 CD84 连接增强了 F10 表达。前列腺肿瘤中 FX、CD84 和 PAR2 水平升高与 CRPC 患者生存率较差相关。这项研究提供了 FXa 直接促进癌症的证据，并强调了 PMN-MDSC 用于癌症治疗的其他靶点。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。
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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.