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

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.