Colon-Restricted Phosphatase and Tensin Homolog Deleted From Chromosome 10 Haploinsufficiency Models - PI3K Pathway-Driven Invasion in Colorectal Cancer

Sep 23, 2026

CDX2P-Cre–based colon-restricted genetically engineered mouse models recapitulate multiple histological subtypes of colonic neoplasia, enabling genotype–phenotype dissection in colorectal tumorigenesis. Pten haploinsufficiency accelerates Apc-driven invasive adenocarcinoma through mTORC1 activation, and human colorectal cancers show phosphoinositide 3-kinase pathway activation associated with invasive progression. The work combines multi-omics, organoid rapamycin testing, and NBI-guided human biopsy analysis to link early invasion with PI3K–AKT–mTOR signaling.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages23

Reading Time58 min

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Background & Aims

Methods

Results

Conclusions

ORIGINAL RESEARCH Colon-Restricted Phosphatase and Tensin Homolog Deleted From Chromosome 10 Haploinsufficiency Models Phosphoinositide 3-Kinase Pathway-Driven Invasion in Colorectal Cancer Haruki Sada, 1 ,2 ,* Hiroaki Niitsu,3 ,* Yuji Urabe,4 Hikaru Nakahara,3 Masatoshi Kochi,2 ,5 Naoya Sakamoto,6 ,7 Yusuke Sotomaru,8 Hirotaka Tashiro,1 Shiro Oka,4 Hideki Ohdan,2 Eric R. Fearon,9 and Takao Hinoi2 ,3 1Department of Surgery, NHO Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan; 2Department of Gastroenterological and Transplantation Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Hiroshima, Japan; 3Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, Japan; 4Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Hiroshima, Japan; 5Department of Gastroenterological Surgery, NHO Higashihiroshima Medical Center, Higashihiroshima, Hiroshima, Japan; 6Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East Japan, Kashiwa, Chiba, Japan; 7Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan; 8Natural Science Center for Basic Research and Development, Hiroshima University, Higashihiroshima, Hiroshima, Japan; and 9Department of Internal Medicine, Human Genetics, and Pathology, University of Michigan, Ann Arbor, Michigan SUMMARY CDX2P-Cre–based genetically engineered mouse models for colonic neoplasia recapitulate diverse histological subtypes. Among them, Pten haploinsufficiency accelerates Apcdriven invasive adenocarcinoma through mechanistic target of rapamycin complex 1 activation. Consistently, human colorectal cancers exhibit phosphoinositide 3-kinase pathway activation associated with invasive progression. WHAT YOU NEED TO KNOW Background: CDX2P-Cre–based colon-restricted genetically-engineered mouse models (GEMMs) provide a robust platform for dissecting genotype–phenotype relationships in colorectal tumorigenesis. However, the molecular determinants governing the early transition to invasive adenocarcinoma remain unclear. Impact: Apc loss plus Pten haploinsufficiency generates a reproducible invasive phenotype in colon-restricted GEMMs. Parallel NBI-guided human biopsies demonstrate phosphoinositide 3-kinase (PI3K) pathway abnormalities linked to early invasive transformation in colorectal tumor evolution. 2 Sada et al Cellular and Molecular Gastroenterology and Hepatology Vol. 20, Iss. 9 Future Directions: This trackable GEMM enables longitudinal dissection of PI3K– mechanistic target of rapamycin–driven early invasion and offers a preclinical platform to evaluate rational intervention strategies aimed at intercepting colorectal cancer progression. BACKGROUND & AIMS: The multistep accumulation of driver gene mutations is associated with early-stage colorectal tumorigenesis. To observe the phenotype-genotype correlation, we developed a series of genetically engineered mouse models based on Apc inactivation led by CDX2P-Cre and found invasive adenocarcinomas developed by inducing the loss of one Pten copy with Apc inactivation in the colonic epithelium. Here, we aimed to study the mechanisms underlying Ptenhaploinsufficiency and its clinical relevance. METHODS: Tumor number, volume, and histology were compared between CDX2P-Cre;Apcflox/+ (CPC;Apc) and CDX2PCre;Apcflox/+;Ptenflox/+ (CPC;ApcPten) mice, and a multi-omics analysis was used to investigate the mechanism of the invasive phenotype in CPC;ApcPten mice. Rapamycin was administered to tumor organoids and in vivo to evaluate its dependency on the ATK serine-threonine protein kinase (AKT) - mechanistic target of rapamycin complex 1 (mTORC1) pathway. We also performed phylogenetic analysis of tumor evolution during human colorectal carcinogenesis using multiple targeted biopsies.

FAQs

What mouse model system was used to study colorectal tumorigenesis?

CDX2P-Cre–based colon-restricted genetically engineered mouse models were used, with Apc inactivation and Pten haploinsufficiency introduced to model invasive adenocarcinoma development.

How does Pten haploinsufficiency influence tumor progression in the study?

Loss of one Pten copy reduces Pten expression and activates the AKT–mTORC1 signaling pathway, promoting invasive transformation in the colon epithelium.

What evidence links PI3K pathway abnormalities to early invasion in humans?

In clinical biopsies, PI3K genetic alterations were predominantly observed during the transition from tubular adenoma to adenocarcinoma, aligning with early invasive transformation in tumor evolution.

Sep 23, 2026

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