GATA4 loss promotes mutant Kras-driven pancreatic ductal adenocarcinoma in the absence of canonical precursor lesions [ChIP-Seq]

Using genetic mouse models we show that, in contrast to GATA6, GATA4 is dispensable for the maintenance of acinar homeostasis in the adult pancreas. Deletion of Gata4 in mice expressing mutant Kras in the embryonic pancreas (KG4C) leads to PDAC development in the absence of acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasias (PanINs), or other canonical precursor lesions present in Gata4-proficient (KC) mice.

Similar observations were made when Gata4 was selectively inactivated in adult, Kras-mutant, acinar cells, We identify Pale Acinar Lesions (PALes) as a previously unrecognized pancreatic lesion, distinct from ADM and PanINs, present in KC and KG4C mice but not in control mice. PALes display weak expression of acinar and ductal markers and lack mucins; they have lower proliferation rates than PanINs. RNA-seq and ChIP-seq reveal that GATA4 and GATA6 partially share genomic binding sites and transcriptomic effects, but they exert opposing influences on mutant Kras–induced, hematopoietic cell–dependent, transcriptional inflammatory signatures.