Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths, with the majority of cases resulting from activating mutations in the KRAS oncogene. Low-grade pancreatic intraepithelial neoplasias (PanINs) form prior to malignant transformation, and these early lesions carry activating KRAS mutations. In murine models of KRAS-driven PDAC, PanIN formation corresponds with activation of a prooncogenic transcriptional pathway that induces expression of multiple genes, including the gene encoding immediate early response 3 (IER3). Maria Noé Garcia and colleagues at the Centre de Recherche en Cancérologie de Marseille determined that IER3 expression is minimal in healthy pancreatic acinar cells, but prominent in PanIN lesions in both PDAC patients and in murine models. In human pancreatic cancer cells, IER3 promoted ERK1/2 phosphorylation by inhibiting phosphatase PP2A activity. In murine models of KRAS-driven PDAC, pancreatic inflammation induced IER3 expression and promoted PanIN formation and progression to PDAC; however, pancreatitis-induced tumorigenesis was limited in animals lacking IER3. Together, these results indicate that induction of IER3 in early pancreatic lesions promotes malignant transformation in KRAS-driven PDAC by sustaining ERK1/2 phosphorylation. The accompanying image shows pancreas tissue from KrasG12D mice (left) and IER3-deficent KrasG12D mice (right) at 40 weeks of age. PanIN formation is evident in KrasG12D mice, but not in IER3-deficient KrasG12D animals. Sections are stained for CK19 (green) and amylase (red).
Activating mutations in the
Maria Noé Garcia, Daniel Grasso, Maria Belen Lopez-Millan, Tewfik Hamidi, Celine Loncle, Richard Tomasini, Gwen Lomberk, Françoise Porteu, Raul Urrutia, Juan L. Iovanna