Coagulation factor X promotes resistance to androgen-deprivation therapy in prostate cancer

IF 48.8 1区 医学 Q1 CELL BIOLOGY
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, Andrea Alimonti
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引用次数: 0

Abstract

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.

Abstract Image

凝血因子 X 可增强前列腺癌患者对雄激素剥夺疗法的抵抗力
虽然高凝状态通常与恶性肿瘤有关,但凝血因子是否直接影响肿瘤细胞的增殖仍不清楚。在此,我们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),报告了免疫抑制性中性粒细胞(PMN-MDSCs)是凝血因子 X(FX)的一个关键肝外来源。通过激活蛋白酶激活受体2(PAR2)和肿瘤细胞中的ERK1/2磷酸化,TME内的FX激活可增强雄激素依赖性肿瘤的生长。遗传和药物抑制 Xa 因子(FXa)可拮抗 PMN-MDSCs 的致癌活性,减少肿瘤进展,并与恩杂鲁胺疗法协同作用。耐人寻味的是,F10 高的 PMN-MDSCs 可表达表面标记 CD84,而 CD84 结扎可增强 F10 的表达。前列腺肿瘤中 FX、CD84 和 PAR2 水平的升高与 CRPC 患者生存率的降低有关。这项研究提供了 FXa 直接促进癌症的证据,并突出了 PMN-MDSCs 治疗癌症的其他靶点。
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来源期刊
Cancer Cell
Cancer Cell 医学-肿瘤学
CiteScore
55.20
自引率
1.20%
发文量
179
审稿时长
4-8 weeks
期刊介绍: Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.
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