Abstract 2374: Early metabolic rewiring of prostate cancer cells triggered by bone progenitors defines survival of metastatic prostate cancer
Authors: Sanchis Pablo , Anselmino Nicolas , Lavignolle Rosario , Sabater Agustina , Labanca Estefania , Bizzotto Juan , Lage-Vickers Sofia , Pascual Gaston , Seniuk Rocio , Toro Ayelen , Navone Nora , Cotignla Javier , Vazquez Elba , Gueron Geraldine 
Published: June 2022

Abstract
Bone hosts the 88% of Prostate Cancer (PCa) metastases and no curative therapy is currently available for this stage. Arrival of PCa cells to the bone homing organ is accompanied by a metabolic adaptation, which may be mediated by bone secreted factors. Herein, we sought to identify key metabolic genes fueling PCa bone metastasis and soluble factors secreted by bone cells leading to the metabolic rewiring of tumoral cells. By an indirect transwell co-culture system of PCa (PC3) and bone progenitor cells (MC3T3, pre-osteoblasts; or Raw264.7, pre-osteoclasts) we analyzed the transcriptome (RNA-seq) of PC3 cells modulated by soluble factors released from bone precursors. GSEA showed a strong activation of lipid metabolism, including PPAR and PI3K-Akt pathways, fat absorption and digestion. We then performed a Principal Component Analysis using transcriptomic data from human PCa and bone metastasis samples (GSE74685), showcasing that those metabolic genes that appeared significantly dysregulated in the co-culture model could accurately cluster samples by their tissue of origin in two defined groups: primary PCa and bone metastasis. This result was confirmed by an unsupervised clustering analysis, highlighting that the transcriptional metabolic profile triggered in the in vitro model has a clinical correlate in human bone metastasis samples. Interestingly, when performing a survival analysis for those genes in the SU2C-PCF dataset, we observed that 4 lipid-associated genes, PPARA, VDR, SLC16A1 and GPX1, correlated with a shorter overall survival time, and appeared as independent risk-predictors of death (HR: 4.96, 2.85, 3.93 and 3.67, respectively; P&lt;0.05). These results prompted us to evaluate the communication axis by which the expression of the lipid transcriptomic signature is regulated in PC3 cells co-cultured with bone progenitor cells. We performed an Ingenuity Pathway Analysis (QIAGEN) showing that the tumoral Protein Kinase A (PKA) appears as a master regulator of this signature. Accordingly, when we treated PC3 cells with the conditioned media (CM) of PC3 grown alone or the co-culture, we observed a decreased ATP content in the latter compared with controls, which is restored upon PKA inhibition, confirming the role of this kinase in the metabolic phenotype of co-cultured cells. Finally, secretome analysis (ESI-MS/MS) of CM from the co-cultures displayed relevant soluble factors secreted by bone progenitors (Col1a1, Fn1) which are directly linked to PKA activity. Overall, we identified an early lipid-related gene signature in PCa cells triggered by the dialogue with bone cells, enough to discriminate metastatic human PCa from primary tumors and critical for PCa survival. This signature may respond to released soluble bone factors through tumoral cell PKA activation. Our findings pinpoint new attractive metabolic druggable targets to halt disease progression.
Citation Format: Pablo Sanchis, Nicolas Anselmino, Rosario Lavignolle, Agustina Sabater, Estefania Labanca, Juan Bizzotto, Sofia Lage-Vickers, Gaston Pascual, Rocio Seniuk, Ayelen Toro, Nora Navone, Javier Cotignla, Elba Vazquez, Geraldine Gueron. Early metabolic rewiring of prostate cancer cells triggered by bone progenitors defines survival of metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2374.