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 3

Accelerated fibrosis and leukocytic infiltration associated with PanINs in mice expressing oncogenic KRAS in the setting of ICMT deficiency.

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Accelerated fibrosis and leukocytic infiltration associated with PanINs ...
(A) Masson’s trichrome staining of sections of fixed, paraffin-embedded pancreas from 2-month-old mice of the indicated genotypes. The arrow indicates fibrosis surrounding PanIN in pancreas from an Icmtflx/+;Pdx1-Cre;LSL-KrasG12D mouse, while the asterisk indicates more extensive fibrosis in ICMT-deficient pancreas. Scale bars: 200 μm. (B) Percentage of fibrotic areas in five low-power fields (mean ± SEM, n = 8, P < 0.05). (C) Frozen sections of pancreata from 2-month-old mice of the indicated genotypes stained by immunofluorescence for CD45 (leukocyte common antigen) and counterstained with Hoechst to mark nuclei. Also shown in the bottom panels are H&E stains of adjacent frozen sections. Scale bars: 100 μm. (D) Quantification of the average amount of CD45 staining per frozen section (five sections per mouse). Data shown are the mean of two age-matched mice for each genotype.