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.
Cancer cell. 2024 Sep 16 [Epub ahead of print]
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
Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, CH6900 Lugano, Switzerland., Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, CH6900 Lugano, Switzerland; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padova, Italy., Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, CH6900 Lugano, Switzerland; Section of Oncology, Department of Medicine, University of Verona, 37134 Verona, Italy; Medical Oncology Unit, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, CH6500 Bellinzona, Switzerland; Veneto Institute of Molecular Medicine, 35129 Padova, Italy., Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, CH6900 Lugano, Switzerland; Section of Oncology, Department of Medicine, University of Verona, 37134 Verona, Italy., Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, CH6900 Lugano, Switzerland; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy., The Institute of Cancer Research, The Royal Marsden Hospital, London SW3 6JJ, UK., Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Department of Immunoregulation, Immunology and Immunotherapy Division, Center of Molecular Immunology, La Habana 3GGH+C9G, Cuba., Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Department of Medicine, University of Padova, 35121 Padova, Italy., Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Urology Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy., Urology Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy., Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Department of Medicine, Surgical Pathology Unit, University of Padova, 35121 Padova, Italy., Department of Medicine, Surgical Pathology Unit, University of Padova, 35121 Padova, Italy., Department of Pathology and Molecular Pathology, University Hospital Zurich (USZ), 8091 Zurich, Switzerland., Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy., Medical Oncology Unit, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, CH6500 Bellinzona, Switzerland; Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy., Cancer Risk Factors and Lifestyle Epidemiology Unit - ISPRO, 50139 Florence, Italy., Medical Oncology Unit, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, CH6500 Bellinzona, Switzerland., Università della Svizzera Italiana, Faculty of Biomedical Sciences, CH6900 Lugano, Switzerland; Medical Oncology Unit, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, CH6500 Bellinzona, Switzerland., Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA., Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, CH6900 Lugano, Switzerland; Medical Oncology Unit, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, CH6500 Bellinzona, Switzerland; Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Department of Medicine, University of Padova, 35121 Padova, Italy; Department of Health Sciences and Technology (D-HEST) ETH Zurich, 8092 Zurich, Switzerland. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/39303726