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

摘要

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(Delta 8/Delta 8) 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-kappa B and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis.