Germ-line mutations in LKB1 are associated with Peutz–Jeghers syndrome (PJS) — a disorder that is characterized by a predisposition to gastrointestinal polyposis and cancer. The pathogenesis of PJS and the role of LKB1 in this process are not well understood, and a new mouse model has only begun to reveal how complex this disease really is.

PJS is an unusual hereditary cancer syndrome. Although germ-line mutations in LKB1 are associated with a predisposition to cancer, the gene is rarely mutated or epigenetically silenced in sporadic tumours. The intestinal polyps that develop in PJS patients are not highly malignant, and it is not clear whether they are precursors to the carcinomas that these patients eventually develop. To investigate these paradoxical features of PJS, Bardeesy et al. used the Cre-lox system to generate mice that carry a conditional Lkb1 allele. Lkb1-null mice died during embryonic development, whereas Lkb1+/− mice developed intestinal polyps that were identical to those seen in humans with PJS.

So what happens at the cellular level in these mice? Lkb1 is highly expressed by mouse embryonic fibroblasts. After about nine passages, normal fibroblasts undergo growth arrest, but Lkb1-null cells continued growing even after 40 population doublings, indicating a resistance to passage-induced senescence. Although passage-induced senescence is typically attributed to INK4A or p53 activity, these signalling pathways remained intact in Lkb1-null fibroblasts.

Lkb1-null fibroblasts were also resistant to transformation by activated Hras. This phenotype is consistent with the low incidence of Ras mutations found in PJS polyps. The authors performed transcriptional profiling on Lkb1-null cells, and observed alterations in the expression pattern of secreted signalling molecules and regulators of the extracellular matrix, so Lkb1-deficient cells might help create a permissive environment for tumour growth.

On the surface, the resistance to Ras transformation observed in Lkb1-null cells seems to contradict the polyposis and carcinoma-prone condition that is associated with LKB1 deficiency. On the other hand, PJS polyps themselves rarely show features of dysplasia, and LKB1 mutations are only rarely found in tumours in individuals who do not carry germ-line mutations in this gene. One possible explanation for these seemingly contradictory observations is that although LKB1 loss deregulates growth, there might only be certain oncogenic events that can fully transform these cells. Since PJS patients have a high incidence of carcinomas, the timing of LKB1 mutation might also affect outcome. The authors propose that loss of LKB1 in normal cells could result in the formation of benign tumours, whereas loss in advanced neoplasms could promote malignant progression.