p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer

Abstract

Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRAS^G12D-driven PC tumorigenesis. iASPP suppresses PC onset driven by KRAS^G12D alone or KRAS^G12D in combination with mutant p53^R172H. iASPP deletion limits acinar-to-ductal metaplasia (ADM) in vitro but accelerates inflammation and KRAS^G12D-induced ADM, pancreatitis and PC tumorigenesis in vivo. KRAS^G12D/iASPP^Δ8/Δ8 tumours are well-differentiated classical PCs and their derivative cell lines form subcutaneous tumours in syngeneic and nude mice. Transcriptomically, either iASPP deletion or p53 mutation in the KRAS^G12D background altered the expression of an extensively overlapping gene set, comprised primarily of NF-κB and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis.