Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression
Helen Court, … , Martin O. Bergö, Mark R. Philips
Helen Court, … , Martin O. Bergö, Mark R. Philips
Published October 8, 2013
Citation Information: J Clin Invest. 2013;123(11):4681-4694. https://doi.org/10.1172/JCI65764.
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Research Article Oncology

Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

Abstract

RAS is the most frequently mutated oncogene in human cancers. Despite decades of effort, anti-RAS therapies have remained elusive. Isoprenylcysteine carboxylmethyltransferase (ICMT) methylates RAS and other CaaX-containing proteins, but its potential as a target for cancer therapy has not been fully evaluated. We crossed a Pdx1-Cre;LSL-KrasG12D mouse, which is a model of pancreatic ductal adenocarcinoma (PDA), with a mouse harboring a floxed allele of Icmt. Surprisingly, we found that ICMT deficiency dramatically accelerated the development and progression of neoplasia. ICMT-deficient pancreatic ductal epithelial cells had a slight growth advantage and were resistant to premature senescence by a mechanism that involved suppression of cyclin-dependent kinase inhibitor 2A (p16INK4A) expression. ICMT deficiency precisely phenocopied Notch1 deficiency in the Pdx1-Cre;LSL-KrasG12D model by exacerbating pancreatic intraepithelial neoplasias, promoting facial papillomas, and derepressing Wnt signaling. Silencing ICMT in human osteosarcoma cells decreased Notch1 signaling in response to stimulation with cell-surface ligands. Additionally, targeted silencing of Ste14, the Drosophila homolog of Icmt, resulted in defects in wing development, consistent with Notch loss of function. Our data suggest that ICMT behaves like a tumor suppressor in PDA because it is required for Notch1 signaling.

Authors

Helen Court, Marc Amoyel, Michael Hackman, Kyoung Eun Lee, Ruliang Xu, George Miller, Dafna Bar-Sagi, Erika A. Bach, Martin O. Bergö, Mark R. Philips

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Figure 2

Acinar-to-ductal metaplasia contributes to PanINs in ICMT-deficient pancreata.

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Acinar-to-ductal metaplasia contributes to PanINs in ICMT-deficient panc...
(A) Frozen sections of pancreata from 2-month-old mice of the indicated genotypes were stained by immunofluorescence for cytokeratin 19 (CK19, a ductal marker, green) and amylase (an acinar marker, red) and counterstained with Hoechst (blue) to mark nuclei. Whereas staining in Icmtflx/+;Pdx1-Cre;LSL-KrasG12D pancreata revealed strict segregation of cells that stained for each marker, some cells associated with PanINs in Icmtflx/flx;Pdx1-Cre;LSL-KrasG12D pancreata stained for both markers (arrows). Scale bars: 50 μm. (B) Percentage of cells positive for both amylase and CK19 in five low-power fields examined for each genotype (mean ± SEM, n = 3, P < 0.05). (C) H&E-stained sections of pancreata from the same mice showing PanINs. The PanINs in the ICMT-deficient pancreas more frequently revealed areas in which acinar cells appeared to be differentiating into ductal cells (arrows).