Inhibition of HIF1 signaling as a therapeutic option for metastatic castration-resistant prostate cancer.

Metastatic prostate cancer is a deadly disease, due to the lack of efficient therapies. PTEN and TP53 are the most frequently mutated tumor suppressor genes in metastatic PCa, but the molecular and cellular events underlying tumor aggressivity and treatment resistance are incompletely understood. We have previously shown that Pten/Trp53(i)-/- mice, in which both Pten and Trp53 are selectively inactivated in prostatic luminal cells at adulthood, develop aggressive intraductal prostate carcinoma (IDC) and liver metastases. By combining single cell and spatial transcriptomic, as well as flow cytometry analyses, we now demonstrate that prostatic tumors of such mice are hypoxic and are within a complex immune infiltrate, including neutrophils, as well as TREM2+ macrophages and CCR2+ myeloid cells. Moreover, we uncovered that genetic inactivation of Hif1a in PECs of Pten/Trp53(i)pe-/- mice or pharmacological inhibition of HIF1 signaling does not impair IDC formation and epithelial cell plasticity induced by Trp53 deficiency, but promotes neutrophil chemotaxis. In addition, systemic HIF1 inhibition reduces CCR2+ myeloid cell infiltration, and antagonizing these cells or neutrophils overcomes castration resistance in primary tumors and reduces the size of liver metastatic niches. Importantly, we demonstrate that pharmacological HIF1 inhibition also overcomes castration resistance of PTEN/p53-deficient prostatic tumors, and eradicates liver metastatic niches with an increased efficiency compared to the myeloid cells antagonists. Thus, pharmacological inhibition of HIF1 signaling is a promising therapeutic approach for metastatic castration-resistant prostate cancer.