LKB1 modulates lung cancer differentiation and metastasis

Inherited mutation in LKB1 results in the Peutz-Jeghers syndrome (PJS), characterized by intestinal hamartomas and a modestly increased frequency of gastrointestinal and breast cancer1. Somatic inactivation of LKB1 occurs in human lung adenocarcinoma2-4, but its tumor suppressor role in this tissue is unknown. Here we show that somatic Lkb1 deficiency strongly cooperates with somatic K-rasG12D activating mutation to accelerate the development of mouse lung tumorigenesis. Lkb1 deficiency in the setting of K-rasG12D mutation (K-ras Lkb1L/L) was associated with decreased tumor latency and increased tumor aggressiveness including metastasis. Furthermore, tumors from K-ras Lkb1L/L mice demonstrated histologies--squamous, adenosquamous and large cell--not seen with K-rasG12D mutation, Ink4a/Arf inactivation, or p53 inactivation alone or in combination. Experiments in vitro suggest that LKB1 suppresses lung tumorigenesis and progression through both p16INK4a-ARF-p53 dependent and independent mechanisms. These data indicate that LKB1 regulates lung tumor progression and differentiation. Keywords: cancer research