Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. Prostatic intraductal carcinoma (IDC) is a subset of prostate cancer strongly associated with metastatic spreading and a poor outcome (1). Thus, unraveling the mechanisms underlying its aggressiveness might lead to the development of personalized therapies. PTEN and TP53 loss are common genetic alterations in IDC (2). Moreover, recent studies reported that extensive hypoxia is associated with high-risk disease (3), but its contribution to tumor progression is incompletely understood.

We characterized tumor progression in genetically engineered mice, in which Pten and Trp53 are inactivated in prostatic epithelial cells (PECs) at adulthood (Pten/Trp53(i)pe-/- mice) using single-cell and spatial transcriptomic profiling, as well as by flow cytometry. Hypoxia-inducible factor 1 (HIF1) inhibition was achieved by treatment with PX-478 or by genetic inactivation of Hif1a in PECs.

Pten/Trp53(i)pe-/- mice develop intraductal carcinomas (IDC) that disseminate to liver. We uncovered that the cell plasticity and metastatic potential is driven by a crosstalk between PECs and cancer-associated fibroblasts (4). Importantly, IDCs of Pten/Trp53(i)pe-/- mice are characterized by an hypoxic core and Visium Spatial transcriptomic profiling revealed that the hypoxic regions are enriched in immune system-related pathways. Deeper analyses, including cell type inference and flow cytometry, unraveled that the immune infiltrate is mainly composed of immunosuppressive macrophages and neutrophils. Both genetic inactivation and pharmacological inhibition of HIF1 signaling decrease neutrophil infiltrates in prostatic tumors and resensitize them to androgen deprivation. However, only pharmacological HIF1 targeting impairs circulating neutrophil levels and eradicates hepatic micrometastases, indicating a key role of these immune cells in tumor spreading.

Taken together, our study highlights local and systemic interactions of prostatic epithelial cells that contribute to their metastatic dissemination, and opens novel therapeutic avenues for treatment-resistant and metastatic prostate cancer. (1) Böttcher, R. et al., BMC Cancer 18, 8 (2018) (2) Elfandy, H. et al., Molecular Cancer Research 17, 446–456 (2019) (3) Ci, X. et al., BMC Cancer 24, 744 (2024) (4) Yanushko, D. et al., Cell Death and Disease 16, 46 (2025)