Intestinal LKB1 loss drives a pre-malignant program along the serrated cancer pathway

Abstract Peutz-Jeghers syndrome (PJS) is a familial disorder caused by heterozygous inactivating Liver Kinase B1 ( LKB1) mutations that promote gastrointestinal polyposis and enhance cancer susceptibility. How LKB1 -deficiency alters the phenotypical landscape and hierarchical organization of epithelial tissues to mediate increased cancer risk remains poorly understood. Here, we employ small intestinal organoids to investigate these issues for heterozygous and homozygous Lkb1 epithelial loss. We show that Lkb1 loss causes an allele dosage-dependent activation of a transcriptional program for tissue repair that is already induced in stem cell populations and mediates alterations in secretory cell type morphology and positioning. Furthermore, this shift towards a regenerative state omits the need for EGF supplementation, thus inducing niche-independent properties. Strikingly, we uncover that heterozygous loss of Lkb1 is sufficient to push the epithelium into a premalignant program for colorectal carcinogenesis along the serrated pathway, which is further amplified by loss-of-heterozygosity (LOH) or Kras mutations. We conclude that persistent upregulation of a regenerative program due to LKB1 loss alters cellular hierarchy and induces niche independency, which predisposes PJS epithelium to uncontrolled growth along the serrated pathway.