Darya Yanushko

Prostate cancer (PCa)-related deaths are mainly due to metastasis. The increase in de novo metastatic hormone-naive PCa (mHNPCs) highlights the urgent need for biomarkers and treatment strategies. We report in a cohort of French PCa patients that the levels of vitamin D and of prostate-specific antigen, the progression biomarker used clinically, are negatively associated. However, the impact of vitamin D receptor (VDR) signaling on prostate tumorigenesis remains unclear. Mice with PTEN inactivation in prostatic epithelial cells (PECs) at adulthood ( Pten ^(i)pe−/− mice) faithfully recapitulate the human disease. We showed that inactivation of PTEN and VDR in PECs promotes tumor aggressiveness. We demonstrate that VDR loss induces oxidative stress, which in turn enhances PECs proliferation. Moreover, CXCL5 overexpression in PTEN- and VDR-deficient PECs promotes neutrophil infiltration. Importantly, our data highlight elevated circulating neutrophil levels as a biomarker of PCa dissemination and show the potency of targeting neutrophil chemotaxis to reduce liver micrometastases. Overall, this work provides major insights into how vitamin D signaling slows down tumorigenesis and opens new avenues for therapeutic and diagnostic strategies for mHNPC.

Rôle du microenvironnement tumoral dans la progression du cancer de la prostate: Le cancer de la prostate (CaP) est le cancer viscéral le plus fréquent chez l’homme et la deuxième cause de mortalité masculine par cancer. La majorité des décès est causée par les CaP métastatiques car aucun traitement curatif n’existe aujourd’hui pour ces formes. Les gènes PTEN et TP53 sont fréquemment mutés dans des CaP métastatiques et résistants aux traitements. Nos études révèlent que la perte de p53 dans les cellules épithéliales en plus de perte de PTEN conduit à l’acquisition d’une plasticité cellulaire. La mise en place de la plasticité cellulaire requiert un dialogue entre les cellules tumorales et les fibroblastes associés au cancer. De plus, les niches hypoxiques se forment dans le cœur des tumeurs et des neutrophiles immunosuppressifs s’accumulent dans ces niches. L’inhibition du facteur inductible par l’hypoxie HIF1 réduit l’infiltration des neutrophiles dans les tumeurs, ainsi que des monocytes CCR2+ dans le stroma. De plus, ce traitement resensibilise les tumeurs à la déprivation androgénique et éradique les métastases hépatiques. Ainsi, nos travaux identifient plusieurs axes de communication entre les cellules tumorales et le microenvironnement importants pour la dissémination métastatique et la résistance aux traitements, ouvrant sur des nouvelles pistes thérapeutiques.

Metastatic prostate cancer (PCa) remains lethal due to limited effective therapies. PTEN and TP53 are commonly mutated tumor suppressors in metastatic PCa, yet the molecular and cellular mechanisms driving aggressiveness and treatment resistance are not fully understood. We have previously shown that mice with both Pten and Trp53 inactivation in prostate luminal cells at adulthood develop aggressive intraductal prostate carcinoma (IDC) and liver metastases. By combining single-cell and spatial transcriptomics, along with flow cytometry and immunohistochemical analyses, we now reveal that prostatic tumors of such mice are hypoxic and progress within a complex immune microenvironment, including neutrophils, TREM2⁺ macrophages, and CCR2⁺ myeloid cells. Moreover, we uncovered that genetic Hif1a inactivation in prostate luminal cells or pharmacological inhibition of HIF1 signaling in Pten/Trp53 ^(i)pe−/− mice does not prevent IDC formation or epithelial plasticity driven by Trp53 loss, but impairs neutrophil recruitment. In addition, HIF1 inhibition reduces CCR2⁺ myeloid cell infiltration. Importantly, targeting these immune cells sensitizes tumors to androgen deprivation and reduces the size of liver metastatic niches. Moreover, pharmacological HIF1 inhibition not only overcomes castration resistance, but also eliminates metastatic niches, offering a more effective approach than direct myeloid cell blockade. Thus, HIF1 targeting emerges as a promising therapy for metastatic castration-resistant PCa.

The immune landscape of healthy prostate and its alterations during prostate cancer (PCa) progression remain poorly characterized. Using scRNA-sequencing and multiparametric flow-cytometry analysis, we comprehensively characterized immune cells in wild-type and PTEN^(i)pe-/- mouse prostates, a model that closely recapitulates human PCa. PCa in PTEN^(i)pe-/- is marked by the recruitment of tumor-associated neutrophils (TANs), which represent the dominant immune cell population and resolved into eight distinct states, Trem2⁺ tumor-associated-macrophages (TAMs), and exhausted CD8⁺ T cells. Trem2⁺ TAMs differ from the three main resident macrophage populations in the healthy prostate, exhibiting a strong metabolic and immunosuppressive signature, likely driven by the MIF/HIF1A-signaling axis. This study provides the first detailed characterization of immune cells in the healthy mouse prostate and reveals changes in the immune landscape associated with prostate cancer progression.

Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. The tumor suppressor genes PTEN and TP53 are frequently mutated in prostate cancer and are predictive of early metastatic dissemination and unfavorable patient outcomes. The progression of solid tumors to metastasis is often associated with increased cell plasticity, but the complex events underlying TP53-loss-induced disease aggressiveness remain incompletely understood. Using genetically engineered mice, we show that Trp53 deficiency in Pten-null prostatic epithelial cells (PECs) does not impact early cell proliferation and neoplasia formation, nor growth arrest and senescence entry at a later time. However, Trp53-deficiency enhances invasive adenocarcinoma development and promotes metastatic cell dissemination. Importantly, our single-cell transcriptomic and chromatin accessibility analyses combined with histological examinations uncovered an epithelial cell population characterized by an induction of Jak/Stat3 signaling and displaying mesenchymal features. Moreover, we show that the transcriptomic signature of this cell population is prominent in tumors of patients with high-risk prostate cancer or metastatic disease. In addition, our in vivo and organoid-based experiments provide evidence that PEC plasticity occurs through bi-directional communication with cancer-associated fibroblasts (CAFs). Thus, our study demonstrates that p53 loss induces a protumorigenic crosstalk between PECs and CAFs, and identifies new vulnerabilities that might be targeted to limit cancer progression.