biostudies-literatureShin AEAmerican Cancer SocietyNIDDK NIH HHSNCI NIH HHSNational Institutes of HealthNIH HHSe186035https://www.ebi.ac.uk/biostudies/studies/S-EPMC11996871biostudies-literatureUnknown135(8)Colorectal cancer (CRC) remains a leading cause of cancer death because of metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively active Pik3ca that form intestinal tumors progressing to liver metastases with an intact immune system, addressing the limitations of previous Pik3ca-mutant models, including long tumor latency, mixed histology, and lack of distant metastases. The PI3Kα-specific inhibitor alpelisib reduced migration and invasion in vitro and metastasis in vivo. We present a comprehensive analysis The Journal of clinical investigationLIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models.PMC11996871K08CA245192R01CA277795PF-23-1151788-01-DMCP30CA013696P30 DK132710P30 CA013696S10 OD020056K08 CA245192L30CA264714-01PF-23-1149774-01-MMR01 CA277795L30 CA2647145P30DK132710Nishiwaki NVasan NCohen DASugiura KDe DFlashner SPRustgi AKKlein-Szanto AJGabre JTSims PALengner CJShin AEKariuki SWfalseLIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models.Colorectal cancer (CRC) remains a leading cause of cancer death because of metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively active Pik3ca that form intestinal tumors progressing to liver metastases with an intact immune system, addressing the limitations of previous Pik3ca-mutant models, including long tumor latency, mixed histology, and lack of distant metastases. The PI3Kα-specific inhibitor alpelisib reduced migration and invasion in vitro and metastasis in vivo. We present a comprehensive analysis 2025-01-01T00:00:00Z2025 Apr2026-06-01T17:49:56.131Z2025-06-26T03:06:27.252ZS-EPMC119968713980849710.1172/JCI186035