| Autor: |
Pablo Sanchis, Nicolas Anselmino, Sofia Lage-Vickers, Agustina Sabater, Rosario Lavignolle, Estefania Labanca, Peter D. A. Shepherd, Juan Bizzotto, Ayelen Toro, Antonina Mitrofanova, Maria Pia Valacco, Nora Navone, Elba Vazquez, Javier Cotignola, Geraldine Gueron |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Cancers; Volume 14; Issue 9; Pages: 2083 |
| ISSN: |
2072-6694 |
| DOI: |
10.3390/cancers14092083 |
| Popis: |
Metastatic prostate cancer (PCa) cells soiling in the bone require a metabolic adaptation. Here, we identified the metabolic genes fueling the seeding of PCa in the bone niche. Using a transwell co-culture system of PCa (PC3) and bone progenitor cells (MC3T3 or Raw264.7), we assessed the transcriptome of PC3 cells modulated by soluble factors released from bone precursors. In a Principal Component Analysis using transcriptomic data from human PCa samples (GSE74685), the altered metabolic genes found in vitro were able to stratify PCa patients in two defined groups: primary PCa and bone metastasis, confirmed by an unsupervised clustering analysis. Thus, the early transcriptional metabolic profile triggered in the in vitro model has a clinical correlate in human bone metastatic samples. Further, the expression levels of five metabolic genes (VDR, PPARA, SLC16A1, GPX1 and PAPSS2) were independent risk-predictors of death in the SU2C-PCF dataset and a risk score model built using this lipid-associated signature was able to discriminate a subgroup of bone metastatic PCa patients with a 23-fold higher risk of death. This signature was validated in a PDX pre-clinical model when comparing MDA-PCa-183 growing intrafemorally vs. subcutaneously, and appears to be under the regulatory control of the Protein Kinase A (PKA) signaling pathway. Secretome analyses of conditioned media showcased fibronectin and type-1 collagen as critical bone-secreted factors that could regulate tumoral PKA. Overall, we identified a novel lipid gene signature, driving PCa aggressive metastatic disease pointing to PKA as a potential hub to halt progression. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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