GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE302nnn/GSE302659/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE302659GEOGSEfalseIntestinal LKB1 loss drives a pre-malignant program along the serrated cancer pathway [bulkRNA-seq]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.2026/04/20GSE302659GSM9108390GSM9108391GSM9108392GSM9108393GSM9108394GSM9108395GSM9108396GSM9108375GSM9108397GSM9108376GSM9108398GSM9108399GSM9108377GSM9108410GSM9108378GSM9108379GSM9108380GSM9108381GSM9108382GSM9108383GSM9108384GSM9108385GSM9108405GSM9108406GSM9108407GSM9108408GSM9108409GSM9108386GSM9108387GSM9108388GSM9108400GSM9108389GSM9108401GSM9108402GSM9108403GSM91084041905730172302659Mus musculus[41128695]