Inactivation of CDKN2A-ARF Promotes p53-Independent Remodeling of the PDAC Tumor Microenvironment [RNA-Seq]
The CDKN2A locus, which is frequently deleted in pancreatic ductal adenocarcinoma (PDAC), encodes two tumor suppressors, ARF and INK4A, that may influence tumorigenesis through distinct mechanisms. Distinguishing their individual contributions to cancer could help improve the understanding of PDAC pathogenesis and potentially uncover targetable vulnerabilities. Moreover, while ARF is known to enhance p53 function, defining its p53-independent activities could elucidate new processes that drive PDAC development. Here, we sought to understand ARF function in PDAC suppression. Analysis of gene expression and mutational patterns in human PDAC TCGA data indicated that CDKN2AARF and CDKN2AINK4A are commonly both affected by point mutations and/or deletions, suggesting that their combined inactivation contributes to PDAC development. In genetically engineered mouse models (GEMMs), Arf inactivation accelerated KRASG12D-driven PDAC development, both in the presence and absence of Trp53, demonstrating that ARF is a PDAC suppressor and can act in a p53-independent manner. Transcriptomic analyses of PDACs supported a p53-independent role for ARF, with ARF deficiency promoting extracellular matrix, collagen synthesis/assembly, and epithelial-mesenchymal transition gene expression programs. Accordingly, ARF-deficient PDACs displayed extensive remodeling of the tumor microenvironment (TME), associated with collagen deposition, increased tissue stiffness, and higher fibroblast content – hallmarks of aggressive and treatment-resistant PDAC stroma. Together, this study shows how ARF deficiency associated with CDKN2A inactivation sculpts the PDAC TME in a p53-independent fashion. Given the central role of the TME in PDAC progression and therapeutic resistance, these findings may provide insight critical for improving therapeutic interventions for PDAC. Overall design: RNA-Seq was performed on pancreatic ductal adenocarcinoma (PDAC) tumors originating from mouse models of acinar cell-derived (Ptf1aCreER) of the following genotypes KT;KPT; KAT; KPAT. K = KrasLSL-G12D/+; T = R26LSL-tdTom/LSL-tdTom; P = Trp53fl/fl; A = Cdkn2A-Arf fl/fl