Prostate cancer: new discovery at IOR on resistance to hormonal therapies

The Molecular Oncology research group, led by Prof. Andrea Alimonti at the Institute of Oncology Research (IOR, affiliated to USI and member of Bios+) has recently discovered that a factor involved in blood coagulation, Factor X, directly promotes resistance to hormonal therapies in preclinical models and is associated with poor survival in  metastatic castration-resistant prostate cancer (mCRPC) patients. This study also demonstrated that blockade of Factor X enhances the efficacy of current hormonal therapies in multiple mouse models of prostate cancer. 

Castration-resistant prostate cancers (CRPC) are highly inflamed tissues commonly infiltrated by immunosuppressive neutrophils, antagonizing antitumor immunity and promoting therapy resistance. The team led by Prof. Alimonti has pioneered research in the characterization of these immunosuppressive neutrophils in the context of advanced prostate cancer, highlighting their key role in worsening disease outcome in both preclinical and clinical settings  (Di Mitri et al, Nature, 2014; Calcinotto et al, Nature, 2018; Bancaro et al, Cancer Cell, 2023; Guo et al, Nature, 2023). Intriguingly, the presence of a tumor and systemic inflammation often associate with blood hypercoagulability. Despite the strong association established between coagulation and inflammation, the role of coagulation factors in cancer progression still remains elusive. 

The discovery

Dr. Bianca Calì and colleagues from IOR exploited high-throughput sequencing technologies to extensively characterize the secretory profile of immunosuppressive neutrophils in the tumor microenvironment of castration-resistant prostate cancer. The study unveiled that immunosuppressive neutrophils can release in the prostate tumor microenvironment of both mice and patients affected by CRPC the coagulation factor (Factor X). Therefore, the IOR researcher discovered that immunosuppressive neutrophils are an unexpected source of coagulation factors, which are commonly produced by the liver, in CRPC mouse models and patients.More specifically, the team showed that neutrophil-derived Factor X directly promotes resistance to androgen-deprivation therapy by activating proliferative signals in prostate tumor cells. Intriguingly, high levels of neutrophil-derived Factor X, as well of its receptor expressed on tumor cells (PAR2), associated with poor prognosis in prostate cancer patients. Finally, the administration of specific anticoagulants inhibiting Factor X activity enhanced the efficacy of standard therapies in mouse models. This research reveals a new interplay between coagulation factors, immune cells, and cancer.

The study

The study entitled “Coagulation factor X promotes resistance to androgen-deprivation therapy in prostate cancer” conducted at the IOR has benefited from multiple Swiss and international collaborations, including the Oncology Institute of Southern Switzerland (IOSI), the University Hospital Zurich (USZ), the University of Padova (Italy), the Institute of Cancer Research (ICR/RMH, London, UK) and the Johannes Gutenberg University Medical Center (Mainz, Germany).

To access the full version of the study, please refer to the publication in Cancer Cell: https://doi.org/10.1016/j.ccell.2024.08.018