Dissecting tumor vs. stroma transcriptome in PDAC xenografts: MRP4 as an inductor of stromal activation

SAHORES A*; GANCEDO SN; GONZÁLEZ JF; DE SOUSA-SERRO MG; GÓMEZ N; MAY M.; SHAYO C; DAVIO CA; GONZÁLEZ B

Mar del Plata

Congreso; SAIC; 2022

SAIC

The xenobiotic transporter MRP4/ABCC4 is involved in the regulation of cAMP signaling by extrusion to the extracellular compartment. MRP4 is highly expressed in pancreatic ductal adenocarcinoma (PDAC), and is linked to increased proliferation, a mesenchymal phenotype and poor prognosis. PDACs are characterized by a dense fibrotic (desmoplastic) stroma that promotes tumor progression and chemoresistance. Within the PDAC stroma, there is strong interest in the cancer activated fibroblasts (CAFs), as these cells boost tumor progression. The aim of our study was to evaluate the effect of tumor MRP4 overexpression on the stromal compartment. We established PDAC xenografts by subcutaneous inoculation of BxPC3 cells in NSG mice, with stable transfection of either ABCC4 (MRP4+) or empty vector (mock). These xenografts consist of human parenchyma and murine stroma, mainly composed by fibroblasts. The xenografts transcriptome was evaluated by RNAseq, and the obtained FASTQ files were aligned to human and mouse reference genomes. The obtained BAM files were processed with Xenofilter, an algorithm specifically developed to discriminate human and mouse reads. The mouse count matrix was analyzed with DESeq2, and the differentially expressed genes (DEGs) evaluated for functional enrichment (gene ontology and pathway analysis). We detected 49 DEGs in murine stromal cells from MRP4+ vs. mock xenografts. Particularly, stromal upregulated genes showed significative enrichment (FDR