Abstract
AbstractPeutz-Jeghers syndrome (PJS) is a familial disorder caused by heterozygous inactivating Liver Kinase B1 (LKB1)mutations that promote gastrointestinal polyposis and enhance cancer susceptibility. HowLKB1-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 homozygousLkb1epithelial loss. We show thatLkb1loss 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 ofLkb1is 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 toLKB1loss alters cellular hierarchy and induces niche independency, which predisposes PJS epithelium to uncontrolled growth along the serrated pathway.
Publisher
Cold Spring Harbor Laboratory