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A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
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Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K

Alexander E Yueh1, Susan N Payne2, Alyssa A Leystra3

  • 1Division of Hematology and Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.

Plos One
|February 11, 2016
PubMed

Insights

A common PI3K gene mutation initiates colon cancers similar to human disease, bypassing typical WNT signaling pathways. These PI3K-driven cancers respond to PI3K/mTOR inhibition, showing reduced proliferation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The phosphoinositide 3-kinase (PI3K) pathway is crucial for cellular functions and frequently altered in human cancers.
  • Previous studies established a mouse model for colon cancer initiated by a constitutively active PI3K p110-p85 fusion protein via a non-canonical mechanism.

Purpose of the Study:

  • To investigate if a common human PIK3CA mutation (H1047R) can initiate colon cancers analogous to human disease.
  • To characterize the mechanism of tumor initiation and therapeutic sensitivity in PIK3CA-mutated colon cancers.

Main Methods:

  • Generation of mouse models expressing the Pik3caH1047R mutation, a human hotspot analog.
  • Histopathological analysis of induced tumors to compare with human colon adenocarcinomas.
  • Assessment of tumor response to dual PI3K/mTOR inhibition and analysis of downstream signaling.

Main Results:

  • Mice expressing Pik3caH1047R developed invasive adenocarcinomas resembling human colon cancers.
  • Tumorigenesis occurred via a non-canonical pathway, independent of WNT signaling and lacking nuclear β-catenin.
  • The induced cancers were sensitive to PI3K/mTOR inhibition, with reduced proliferation and signaling observed post-treatment.

Conclusions:

  • The PIK3CA H1047R mutation can directly initiate invasive colon adenocarcinomas through a non-canonical, PI3K-dependent mechanism.
  • These findings highlight the relevance of PI3K pathway mutations in human colon cancer development and suggest therapeutic strategies targeting PI3K/mTOR.

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