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.

致癌 KRAS 激活、炎症和 p53 突变是胰腺癌 (PC) 发展的关键驱动因素。在这里，我们报告 iASPP（一种 p53 抑制剂）作为炎症和致癌 KRAS ^G12D驱动的 PC 肿瘤发生的矛盾抑制剂。 iASPP 抑制由 KRAS ^G12D单独驱动或 KRAS ^G12D与突变体 p53 ^R172H组合驱动的 PC 发作。 iASPP 缺失在体外限制了腺泡到导管化生 (ADM)，但在体内加速了炎症和 KRAS ^G12D诱导的 ADM、胰腺炎和 PC 肿瘤发生。 KRAS ^G12D /iASPP ^Δ8/Δ8肿瘤是分化良好的经典 PC，其衍生细胞系在同基因小鼠和裸鼠中形成皮下肿瘤。转录组学上，KRAS ^G12D背景中的 iASPP 缺失或 p53 突变改变了广泛重叠的基因集的表达，该基因集主要由 NF-κB 和 AP1 调节的炎症基因组成。所有这些都将 iASPP 确定为炎症抑制因子和 PC 肿瘤发生的 p53 独立肿瘤抑制因子。