PKA: a key player for the colonization of the bone niche by prostate cancer cells.

SANCHIS, PABLO; LABANCA, ESTEFANIA; ANSELMINO, NICOLÁS; SABATER, AGUSTINA; SOFIA LAGE VICKERS; BIZZOTTO, JUAN; PASCUALI, GASTON; SENIUK, ROCIO; MITROFANOVA, ANTONINA; LECHUGA, JULIA; VALACCO, MP; TORO, AYELEN; COTIGNOLA, JAVIER; ELBA VAZQUEZ.; GUERON GERALDINE

Torino

Congreso; Molecular OncologyVolume 17: Supplement: EACR 2023: Innovative Cancer Science, 12-15 June 2023, Torino, Italy; 2023

European Association for cancer research

IntroductionThe metastatic cascade is a dynamic scenario where metabolic plasticity is critical for the adaptation of tumor cells to the new organ. Understanding the metabolic rewiring occurring in prostate cancer (PCa) cells in the bone niche is an unmet need underlying metastases’ formation. In this work, we aimed at identifying critical regulatory axes of this process.Material and MethodsWe assessed the transcriptome of PCa cells (PC3) modulatedby soluble factors released by bone precursors (MC3T3 and Raw264.7) in an indirect co-culture system. We validated the transcriptional profile of metabolic genes using open-access datasets. Ingenuity Pathway Analysis (IPA) was used to delineate the regulators of these metabolic genes. Bone secretome was profiled in the conditioned media (CM) by ESI-MS/MS. We validated our results using a PDX pre-clinical model comparing gene expression levels in MDA-PCa-183 growing intrafemorally (i.f.) vs. subcutaneously (s.c.).Results and DiscussionsPC3 cells co-cultured with bone progenitors displayed an activation of lipidic categories, including PPAR-signaling and fat absorption/digestion. Accordingly, PC3 cells treated with the CM of the co-culture had an increased accumulation of neutral lipids as shown by Bodipy 493/503 staining. Unsupervised Clustering analysis using transcriptomic data from human PCa and bone metastatic samples (GSE74685) showed that the metabolic genes deregulated in PC3 by the co-culture accurately clustered samples in primary tumor vs. bone metastasis. Moreover, a signature of 5 lipid-associated genes,PPARA,VDR,SLC16A1, PAPSS2andGPX1, was associated with a 23-fold higher risk of death (SU2C-PCF dataset). Interestingly, this signature was also upregulated in the MDA-PCa-183 PDX growingi.f. vs. s.c., suggesting that there are intrinsic bone factors altering PCa metabolism. IPA revealed that these genes are regulated by the Protein Kinase A (PKA). Accordingly, PKA inhibition led to a downregulation of these genes. Moreover, PC3 cells treated with the CM of the co-culture presented differential ATP levels, that were restored by PKA inhibition. Finally, secretome and protein-protein interaction analyses revealed bone-secreted typeI collagen and Fn1 as factors regulating tumoral PKA activity.ConclusionWe propose a novel lipidic gene signature driving PCa aggressive metastatic disease, triggered by the dialogue with bone cells. This signature is regulated by PKA, which responds tobone-secreted factors, and e