Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression
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
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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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 5

ICMT deficiency accelerates the development of PDA but does not significantly affect the survival of mice expressing oncogenic KRASG12D and dominant-negative p53R172H in the pancreas.

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ICMT deficiency accelerates the development of PDA but does not signific...
(A) Percentage of Icmtflx/+;Pdx1-Cre;LSL-KrasG12D (Icmtflx/+) versus Icmtflx/flx;Pdx1-Cre;LSL-KrasG12D (Icmtflx/flx) mice of the indicated ages that had PDA upon histological examination of the pancreas at necropsy (cohort size = 17). (B) H&E staining of paraffin sections of the pancreas (left) and liver (right) of a 6-month-old Icmtflx/flx;Pdx1-Cre;LSL-KrasG12D mouse that developed metastatic disease. Scale bars: 100 μm. (C) Kaplan-Meier survival curves for mice of the genotypes Icmtflx/+;Pdx1-Cre;LSL-KrasG12D;LSL-p53R172H (Icmtflx/+, n = 15) and Icmtflx/flx;Pdx1-Cre;LSL-KrasG12D;LSL-p53R172H (Icmtflx/flx, n = 13). The curves did not differ significantly. (D) Gross pathology of tumors found in a 6-month-old Icmtflx/+;Pdx1-Cre;LSL-KrasG12D;LSL-p53R172H mouse. Clearly visible are a large tumor at the head of the pancreas (asterisk), liver metastases (arrows), and an enlarged spleen (arrowhead).