Protein Kinase A (PKA) as a master regulator of the early metabolic reprogramming in bone metastatic prostate cancer cells.

SANCHIS, PABLO; ANSELMINO NICOLAS; LAVIGNOLLE ROSARIO; SABATER AGUSTINA; LABANCA ESTEFANIA; BIZZOTO, JUAN; LAGE VICKERS, SOFIA; PASCUAL, GASTON; SENIUK, ROCIO; TORO AYELÉN; NAVONE NORA; COTIGNOLA, JAVIER; ELBA VAZQUEZ; GUERON GERALDINE

Virtual

Congreso; 10th Annual Symposium on Global Cancer Research; 2022

PURPOSE: The arrival of metastatic prostate cancer (PCa) tumor cells to the bone niche requires a metabolic adaptation. We sought to identify metabolic dysregulations fueling PCa metastasis, modulated by bone secreted factors.METHODS: By an indirect co-culture system of PCa (PC3) and bone progenitors (MC3T3, pre-osteoblasts, or Raw264.7, pre-osteoclasts) we assessed the transcriptome of PC3 cells modulated by soluble factors released from bone precursors. We validated the transcriptional profile of metabolic genes in open-access transcriptomic datasets. We performed an Ingenuity Pathway Analysis (IPA) to delineate the regulators of these metabolic genes. Bone secretome was profiled on the conditioned media (CM) by ESI-MS/MS. RESULTS: PC3 cells co-cultured with bone progenitors displayed an activation of lipidic categories, including PPAR-signaling and fat absorption/digestion. Principal Component and Unsupervised Clustering analyses using transcriptomic data from human PCa and bone metastatic samples (GSE74685) showed that the metabolic genes deregulated in PC3 accurately clustered samples in primary tumor or bone metastasis. Moreover, 4 lipid-associated genes, PPARA, VDR, SLC16A1 and GPX1, were associated with a shorter survival time (SU2C-PCF dataset), and were independent risk-predictors of death (P