Tumorigenic supporter

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).

Published September 24, 2014, by Corinne Williams

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IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation
Maria Noé Garcia, Daniel Grasso, Maria Belen Lopez-Millan, Tewfik Hamidi, Celine Loncle, Richard Tomasini, Gwen Lomberk, Françoise Porteu, Raul Urrutia, Juan L. Iovanna
Maria Noé Garcia, Daniel Grasso, Maria Belen Lopez-Millan, Tewfik Hamidi, Celine Loncle, Richard Tomasini, Gwen Lomberk, Françoise Porteu, Raul Urrutia, Juan L. Iovanna
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Research Article Oncology

IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation

Abstract

Activating mutations in the KRAS oncogene are prevalent in pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that pancreatic intraepithelial neoplasia (PanIN) formation, which precedes malignant transformation, associates with the expression of immediate early response 3 (Ier3) as part of a prooncogenic transcriptional pathway. Here, we evaluated the role of IER3 in PanIN formation and PDAC development. In human pancreatic cancer cells, IER3 expression efficiently sustained ERK1/2 phosphorylation by inhibiting phosphatase PP2A activity. Moreover, IER3 enhanced KrasG12D-dependent oncogenesis in the pancreas, as both PanIN and PDAC development were delayed in IER3-deficient KrasG12D mice. IER3 expression was discrete in healthy acinar cells, becoming highly prominent in peritumoral acini, and particularly high in acinar ductal metaplasia (ADM) and PanIN lesions, where IER3 colocalized with phosphorylated ERK1/2. However, IER3 was absent in undifferentiated PDAC, which suggests that the IER3-dependent pathway is an early event in pancreatic tumorigenesis. IER3 expression was induced by both mild and severe pancreatitis, which promoted PanIN formation and progression to PDAC in KrasG12D mice. In IER3-deficient mice, pancreatitis abolished KrasG12D-induced proliferation, which suggests that pancreatitis enhances the oncogenic effect of KRAS through induction of IER3 expression. Together, our data indicate that IER3 supports KRASG12D-associated oncogenesis in the pancreas by sustaining ERK1/2 phosphorylation via phosphatase PP2A inhibition.

Authors

Maria Noé Garcia, Daniel Grasso, Maria Belen Lopez-Millan, Tewfik Hamidi, Celine Loncle, Richard Tomasini, Gwen Lomberk, Françoise Porteu, Raul Urrutia, Juan L. Iovanna

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