PKA ORCHESTRATES THE INTERACTION BETWEEN METASTATIC PROSTATE CANCER CELLS AND THE BONE MICROENVIRONMENT

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

Congreso; LXVIII Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2023

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 transcriptional metabolic profile in vitro has a clinical correlate in human metastatic samples. Further, the expression levels of five metabolic genes (VDR, PPARA, SLC16A1, GPX1 and PAPSS2) were independent risk-predictors of death (SU2C-PCF dataset) and a risk score model including 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 patient-derived xenograft pre-clinical model when comparing the PDX MDA-PCa-183 growing intrafemorally vs. subcutaneously and appears to be under the regulatory control of the Protein Kinase A (PKA), that emerges as a critical factor regulating the PCa-bone crosstalk. Following secretome analyses of conditioned media, we found fibronectin (Fn1) and type-1 collagen (Col1a1) as critical bone-secreted factors that regulate tumoral PKA. Additionally, we found that this kinase is critical for the regulation of key factors governing the metastatic process. We observed that the axis Col1a1-Fn1/PKA drives the expression of osteopontin, and of pro-inflammatory and pro-angiogenic genes. Overall, we identified a novel lipid gene signature regulated by PKA, a central hub of PCa metabolism and bone progression, outlining potential therapeutic targets to halt disease progression.