Our publication describing how LKB1 mutations drive a premalignant state in the intestine is now online at Gastroenterology. The full article can be found here.
Heterozygous mutations in the tumor suppressor LKB1 cause Peutz-Jeghers syndrome (PJS), a hereditary condition characterised by gastrointestinal polyps and increased cancer risk. While LKB1 loss in non-epithelial tissues was previously thought to drive polyp formation, how LKB1 deficiency alters the epithelial landscape to increase cancer susceptibility remained unclear.
Using mouse small intestinal and human colon organoids engineered with heterozygous or homozygous LKB1 loss, we discovered that even a single mutated copy of LKB1 pushes intestinal cells into a premalignant transcriptional program linked to serrated colorectal cancer. This effect is amplified when the remaining healthy LKB1 copy is lost. LKB1-deficient cells display persistent features of regeneration and increased expression of EGFR ligands and receptors, enabling growth that is independent of the usual niche signals.
Furthermore, our LKB1-mutant signature is enriched in sporadic serrated colorectal cancers, and cooperation between LKB1 loss and mutant Kras further accelerates organoid growth and transcriptional changes. These findings provide a mechanistic explanation for the increased colorectal cancer risk in PJS patients and highlight how partial loss of a tumor suppressor can prime cells for malignant transformation.
