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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE303530 | GEO | 2026/05/15

REPOSITORIES: GEO

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Project description:Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen-deprivation remain poorly described despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild type mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin?/Sca-1+/CD49fmed). Here we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumorigenesis. In intact mice, we show that LSCmed prevalence remains low (5-10% of epithelial cells) when prostatic androgen receptor signaling unaltered (malignant Hi-Myc mice) but significantly increases in models exhibiting reduced prostatic androgen receptor signaling, rising up to 30% in premalignant tumors (Pb-PRL mice) and to >80% in castration-resistant prostate tumors driven by Pten loss (Ptenpc-/- mice). LSCmed tolerance to androgen deprivation was demonstrated by their persistence (Ptenpc-/-) or further enrichment (Pb-PRL) 2-3 weeks after castration as evidenced by FACS analysis. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene-expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signaling is markedly decreased, which explains why LSCmed tolerate androgen-deprivation. This also enlightens why Ptenpc-/- tumors are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, BrdU staining revealed massive proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. In all, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.

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

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