The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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Calì , B. et al. Cancer Cell. 42 (10): 1676-1692.e11. (2024).
doi: 10.1016/j.ccell.2024.08.018.
Summary of the findings
Summary of the findingsDespite the latest advancements in the treatment options for prostate cancer (PCa), many patients develop metastatic castration-resistant prostate cancer (mCRPC), characterized by elevated counts of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs).
Single-cell RNA sequencing of the tumor microenvironment (TME) of multiple castration-resistant prostate tumor models has revealed that PMN-MDSCs serve as a significant extra-hepatic source of coagulation factor X (FX). Interestingly, FX activation occurs only within the prostate TME and requires Tissue Factor (TF).
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Active FX (FXa) promotes androgen-independent tumor growth by activating protease-activated receptor 2 (PAR2) and inducing ERK1/2 phosphorylation in tumor cells, both in vitro and in vivo. Conversely, inhibition of FX activity—whether genetically or pharmacologically—reduced the oncogenic effects of PMN-MDSCs, slowed tumor progression, and enhanced the efficacy of enzalutamide in multiple mouse models.
Intriguingly, PMN-MDSCs expressing high FX levels also expressed the surface marker CD84 and showed reduced CXCR2 levels, suggesting an aggressive subset of PMN-MDSCs with decreased sensitivity to CXCR2 inhibitors.
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Clinically, high plasma levels of FX and a specific gene signature associated with FX and CD84 expression in PMN-MDSCs in tumor samples correlate with poorer survival outcomes in PCa patients. Further, immunostaining of human prostate tissue microarrays revealed that PAR2 expression increased with tumor progression, being significantly higher in CRPC compared to hormone-sensitive tumors and benign prostate hyperplasia. Of note, prostate tumors lacking PAR2 were associated with markedly longer disease-free survival in patients with prostate adenocarcinoma.
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Future impact
Several evidence have demonstrated a tight association between hypercoagulability and cancer, highlighting a role for EMT and metastasis formation. The discovery that a coagulation factor can directly support tumor growth and resistance to therapy, independently from the coagulation cascade, underscores the potential for developing new treatment strategies targeting intratumor coagulation factors in prostate cancer. Also, the identification of a gene signature associated with poorer survival, as well as the discovery that elevated plasma levels of FX and high PAR2 tumor expression associate with shorter survival, unveiled a new prognostic role for FX-PAR2 axis in CRPC patients.
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