{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE302nnn/GSE302659/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE302659"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Intestinal LKB1 loss drives a pre-malignant program along the serrated cancer pathway [bulkRNA-seq]","description":"Background & Aims Heterozygous inactivating mutations of Serine Threonine Kinase 11 (STK11)/Liver Kinase B1 (LKB1) are causative to the Peutz-Jeghers syndrome (PJS), a hereditary disease characterized by gastrointestinal hamartomatous polyposis and increased cancer susceptibility. While LKB1 loss-induced polyp formation has been ascribed to non-epithelial tissues, how LKB1 deficiency increases cancer risk of patients by altering the phenotypical landscape and hierarchical organization of epithelial tissues remains poorly understood. Methods Using CRISPR/Cas9, we generated heterozygous and homozygous Lkb1-deficient mouse small intestinal and human colon organoids. These organoids were characterized by an integrated approach that combines imaging, bulk and single-cell RNA sequencing and growth factor dependency assays. Our findings were validated in human PJS-derived tissues using immunohistochemistry and linked to colorectal cancer profiles using the TCGA cancer database. Results Our results reveal that heterozygous Lkb1 loss is sufficient to push intestinal cells into a premalignant transcriptional program associated with serrated colorectal cancer, which is further amplified by loss-of-heterozygosity. This altered epithelial growth state associates with persistent features of regeneration and enhanced EGFR ligand and receptor expression, conferring niche-independent growth properties to Lkb1-deficient organoids. Moreover, our newly generated LKB1-mutant signature is enriched in sporadic serrated colorectal cancer, and synergistic cooperation of Lkb1-deficiency with mutant Kras was experimentally confirmed by assessing organoid growth properties and transcriptomes. Conclusions Heterozygous loss of LKB1 pushes intestinal cells into a chronic regenerative state which is amplified upon loss-of-heterozygosity. Lkb1-deficiency thereby generates fertile ground for serrated colorectal cancer formation in the intestine, potentially explaining the increased cancer risk observed in PJS.","dates":{"publication":"2026/04/20"},"accession":"GSE302659","cross_references":{"GSM":["GSM9108390","GSM9108391","GSM9108392","GSM9108393","GSM9108394","GSM9108395","GSM9108396","GSM9108397","GSM9108375","GSM9108376","GSM9108398","GSM9108399","GSM9108377","GSM9108410","GSM9108378","GSM9108379","GSM9108380","GSM9108381","GSM9108382","GSM9108383","GSM9108384","GSM9108385","GSM9108405","GSM9108406","GSM9108407","GSM9108408","GSM9108409","GSM9108386","GSM9108387","GSM9108388","GSM9108400","GSM9108389","GSM9108401","GSM9108402","GSM9108403","GSM9108404"],"GPL":["19057","30172"],"GSE":["302659"],"taxon":["Mus musculus"],"PMID":["[41128695]"]}}