Bone Progenitors Pull the Strings on the Early Metabolic Rewiring Occurring in Prostate Cancer Cells.

Abstract

Simple SummaryAlmost 90% of prostate cancer metastases occur in bone. The arrival of tumor cells to the homing organ requires a metabolic adaptation to different nutrients and oxygen availability in the new microenvironment to fulfill sustained growth and proliferation rates. In this study, we characterized the alterations in tumor metabolism occurring in human prostate cancer cells when they interact with bone cells. We hypothesized that elucidating how these cells obtain their energy and “building blocks”, and that identifying key determinants underlying this phenomenon, could be a promising strategy to halt disease progression. Accordingly, we discovered five genes related to the metabolism of lipids that play a critical role in the survival of metastatic patients, and we established a communication axis between tumor and bone cells that includes bone-secreted collagen and the tumor Protein Kinase A, which drives the early metabolic reprogramming of metastatic cells.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.