Lipid Metabolism and PKA: Therapeutic Targets in Prostate Cancer Bone Metastasis

PABLO SANCHIS; ESTEFANÍA LABANCA; NICOLAS ANSELMINO; AGUSTINA SABATER; SOFIA LAGE VICKERS; JUAN BIZZOTTO; GASTON PASCUAL; ROCIO SENIUK; JULIA LECHUGA; ANTONINA MITROFANOVA; AYELEN TORO; JAVIER COTIGNOLA; NORA NAVONE; ELBA VAZQUEZ; GERALDINE GUERON

Congreso; PCF Scientific Retreat; 2023

BACKGROUND: Among metastatic prostate cancer (PCa), the incidence of bone metastasis reaches 88% and no curative therapy is currently available for this stage of the disease. As a consequence of the metastatic cascade, the arrival of PCa cells to the bone niche requires a metabolic adaptation to the new microenvironment, which could be mediated by bone-secreted factors. Thus, we hypothesized that, the discovery of novel metabolic gene expression signatures and signaling axis that orchestrate PCa progression in the bone, might be a promising approach for the identification of novel therapeutic druggable targets to prevent metastatic progression. In this work, we aimed at identifying the central hubs regulating the metabolic fate of metastatic PCa cells, and the factors and mechanisms fueling the seeding of PCa in the bone niche.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 using publicly available transcriptomic datasets. We performed an Ingenuity Pathway Analysis (IPA) to pin-point the regulators of these metabolic genes. Bone secretome was assesed on the conditioned media (CM) by ESI-MS/MS. We validated our results using a PDX pre-clinical model comparing gene expression levels in the MDA-PCa-183 growing intrafemorally (i.f.) vs. subcutaneously (s.c.).RESULTS: We observed a strong activation of lipid metabolism, including the PPAR-signaling and fat absorption pathways, in PC3 cells co-cultured with bone progenitors. Accordingly, treatment with the CM of the co-culture promoted lipid accumulation in PC3 cells (Bodipy 493/503 staining). Unsupervised Clustering analysis using transcriptomics data from human PCa and bone metastatic samples (GSE74685) revealed that the metabolic genes deregulated in PC3 by the co-culture accurately clustered samples in primary tumor or bone metastasis. Moreover, we delineated a novel signature of 5 lipid-associated genes, PPARA, VDR, SLC16A1, PAPSS2 and GPX1, that is associated with a 23-fold higher risk of death (SU2C-PCF dataset), which was validated in a PDX pre-clinical model when comparing MDA-PCa-183 growing i.f. vs. s.c. IPA showcased that these genes are regulated by the Protein Kinase A (PKA). Accordingly, the expression of these genes was downregulated by PKA inhibition. Additionally, secretome analyses revealed soluble factors (Col1a1 and Fn1) secreted by bone cells that could regulate PKA activity. Moreover, we observed that the axis Col1a1-Fn1/PKA drives the expression of osteopontin, and of pro-inflammatory and pro-angiogenic genes, key factors orchestrating the metastatic process.CONCLUSION: We discovered a new gene signature associated with the metabolism of lipids that is controlled by PKA, a key regulator of the metabolic rewiring and bone progression of PCa, highlighting new potential avenues for therapeutic interventions.FUNDING ACKNOWLEDGEMENTS: This research was funded by Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación (ANPCyT), Argentina: PICT-2016-0056, PICT-RAICES-2018-02639; PICT-2019-2019-03215; Fundación Florencio Fiorini; Universidad de Buenos Aires, Argentina: 20020170100585BA; NIH/NCI U01 CA224044; NIH NLM R01LM013236 (AM); ACS RSG-21-023-01-TBG (AM); and NJCCR COCR21RBG00 (AM).CONFLICTS OF INTEREST DISCLOSURE STATEMENT: authors declare no conflicts of interest.