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Coagulation Factor X Promotes Resistance to Androgen-Deprivation Therapy in Prostate Cancer - Beyond the Abstract

Prostate cancer (PCa) is a leading cancer diagnosis and cause of death among men. Despite the latest therapeutic advances, patients often progress to metastatic castration-resistant prostate cancer (mCRPC).

This phase is associated with the expansion of immunosuppressive myeloid cells, particularly polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). These cells contribute to chronic inflammation and tumor progression by paracrine mechanisms, partly dependent on IL-23 signaling. Administering a CXCR2 antagonist reduces PMN-MDSC recruitment into the tumor, enhancing chemotherapy and androgen-deprivation therapy efficacy in mouse models and mCRPC patients.

Single-cell RNA-seq analysis of the prostate tumor microenvironment (TME) of castration-resistant prostate cancer unveiled that PMN-MDSCs are a key extra-hepatic source of coagulation factor X (FX). Of note, FX was also one of the most upregulated factors identified in PMN-MDSCs in tumors treated with enzalutamide, the CXCR2 inhibitor AZD5069, and an anti-IL-23 therapeutic antibody. FX activation was found to occur within the prostate TME and required Tissue Factor (TF). Active FX enhanced androgen-independent tumor growth by activating the protease-activated receptor 2 (PAR2) and the phosphorylation of ERK1/2 in tumor cells both in vitro and in vivo. On the contrary, genetic and pharmacological inhibition of FX antagonized the oncogenic activity of PMN-MDSCs, reduced tumor progression, and synergized with enzalutamide therapy in multiple mouse models.

Intriguingly, elevated levels of FX and a specific gene signature related to FX expression in PMN-MDSCs correlate with worse survival in PCa patients. Moreover, immunostaining of human prostate tissue microarrays from PCa patients showed that the expression levels of PAR2 increased with tumor progression, being higher in CRPC than in hormone-sensitive tumors and prostate hyperplasia. Further, prostate tumors negative for PAR2 were associated with significantly longer disease-free survival in patients with prostate adenocarcinoma. Of note, PMN-MDSCs expressing high FX levels were characterized by the expression of the surface marker CD84 and low levels of CXCR2, thus suggesting the existence of an aggressive PMN-MDSCs subset with lower sensitivity to CXCR2 inhibitors.

These results indicate a direct role for PMN-MDSCs derived FX in prostate cancer progression, which is independent of the coagulation cascade, and highlight the potential for new treatment strategies targeting coagulation for CRPC.


Figure legend: Calì al. characterize the significance and therapeutic potential of FXa inhibitors in castration-resistant prostate cancer (CRPC). The artwork metaphorically depicts a puppet theatre, symbolizing the tumor microenvironment (TME). The hand (representing immunosuppressive polymorphonuclear cells, PMNs) controls the behavior of the puppet (representing the prostate cancer epithelium) through the strings (symbolizing secreted factors, including FXa). Scissors signify the efficacy of FXa inhibitors in dampening prostate cancer progression. Image credit: Manuel Colucci, Bianca Calì, Andrea Alimonti.

Written by: Bianca Calì,1 Martina Troiani,1 Silvia Bressan,2 Giuseppe Attanasio,1 Sara Merler,3 Viola Moscarda,4 Simone Mosole,1 Elena Ricci,5 Christina Guo,6 Wei Yuan,6 Lewis Gallagher,6 Arian Lundberg,6 Ilona Bernett,6 Ines Figueiredo,6 Rydell Alvarez Arzola,7 Ernesto Bermudez Abreut,7 Mariantonietta D'Ambrosio,1 Nicolò Bancaro,1 Daniela Brina,1 Sara Zumerle,8 Emiliano Pasquini,1 Martino Maddalena,1 Ping Lai,1 Manuel Colucci,1 Nicolò Pernigoni,1 Andrea Rinaldi,1 Davide Minardi,9 Alessandro Morlacco,10 Fabrizio Dal Moro,10 Marianna Sabbadin,11 Francesca Galuppini,12 Matteo Fassan,12 Jan Hendrik Rüschoff,13 Holger Moch,13 Pasquale Rescigno,14 Edoardo Francini,15 Calogero Saieva,16 Mikol Modesti,17 Jean-Philippe Theurillat,1 Silke Gillessen,18 Petra Wilgenbus,19 Claudine Graf,19 Wolfram Ruf,19 Johann de Bono,6 Andrea Alimonti20
 
  1. Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, CH6900 Lugano, Switzerland.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. The Institute of Cancer Research, The Royal Marsden Hospital, London SW3 6JJ, UK.
  7. Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Department of Immunoregulation, Immunology and Immunotherapy Division, Center of Molecular Immunology, La Habana 3GGH+C9G, Cuba.
  8. Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Department of Medicine, University of Padova, 35121 Padova, Italy.
  9. Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Urology Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
  10. Urology Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
  11. Veneto Institute of Molecular Medicine, 35129 Padova, Italy; Department of Medicine, Surgical Pathology Unit, University of Padova, 35121 Padova, Italy.
  12. Department of Medicine, Surgical Pathology Unit, University of Padova, 35121 Padova, Italy.
  13. Department of Pathology and Molecular Pathology, University Hospital Zurich (USZ), 8091 Zurich, Switzerland.
  14. Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy.
  15. 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.
  16. Cancer Risk Factors and Lifestyle Epidemiology Unit - ISPRO, 50139 Florence, Italy.
  17. Medical Oncology Unit, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, CH6500 Bellinzona, Switzerland.
  18. 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.
  19. 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.
  20. 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.

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