Colon-restricted Pten haploinsufficiency models PI3K pathway-driven invasion in human colorectal cancer

ABSTRACT: Background and 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 Pten haploinsufficiency and its clinical relevance. Methods: Tumor number, volume, and histology were compared between CDX2P-Cre;Apcflox/+ (CPC;Apc) and CDX2P-Cre;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 AKT-mTORC1 pathway. We also performed phylogenetic analysis of tumor evolution during human colorectal carcinogenesis using multiple targeted biopsies. Results: A greater number of tumors developed in CPC;ApcPten mice, half of which invaded the submucosal layer. Although both Apc alleles were inactivated by Cre-LoxP recombination and loss of heterozygosity in tumors, a wild-type Pten allele remained in the tumors of CPC;ApcPten mice, suggesting the haploinsufficient effect of Pten on tumorigenesis. Loss of one Pten copy decreased Pten expression levels and induced downstream activation of the AKT-mTORC1 signaling pathway in CPC;ApcPten mice. Rapamycin administration markedly inhibited tumorigenesis in CPC;ApcPten and CPC;Apc mice. In clinical biopsies, PI3K genetic alteration was predominantly observed during the transition from tubular adenoma to adenocarcinoma. Conclusion:The effect of Pten haploinsufficiency on colonic tumor formation in mice reaffirms the significance of PI3K alterations in tumor evolution in human colorectal cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE310707 | GEO | 2026/07/08

REPOSITORIES: GEO