Lkb1 deletion in a Kras-mutant background causes highly metastatic melanoma in 100% of mice.
Major finding: Lkb1 deletion in a Kras-mutant background causes highly metastatic melanoma in 100% of mice.
Clinical relevance: LKB1 inactivation leads to a YES-dependent expansion of CD24+ tumor cells.
Impact: YES may be a promising therapeutic target in LKB1-deficient melanomas.
LKB1 is a tumor suppressor gene that is somatically inactivated in multiple human cancers, including 10% of melanomas. LKB1 serine/threonine kinase activity can also be suppressed by the activating BRAF mutations that occur in approximately half of all melanomas, suggesting that LKB1 inactivation may be a common event in melanoma. Liu and colleagues therefore sought to explore the role of LKB1 loss in melanoma by conditionally inactivating Lkb1 in murine melanocytes. Interestingly, combining Lkb1 deletion with Kras activation led to melanoma formation with 100% penetrance, whereas either genetic alteration alone was insufficient to induce tumor formation. Furthermore, metastasis was not observed in tumor-bearing mice from other Kras-driven melanoma models with intact LKB1 function. Consistent with these findings, LKB1 deficiency increased melanoma cell migration and invasion in vitro and led to significant upregulation of CD24, a cancer stem cell marker protein with roles in metastasis. Lkb1 knockdown in murine melanomas led to an expansion of CD24+ cells, which formed more metastases than CD24− cells following tail-vein injection. Given a previous observation that LKB1 loss activates SRC family kinases in lung tumors, the authors evaluated these proteins in human melanoma cell lines and found that reduced LKB1 levels were specifically associated with increased phosphorylation of the SRC family kinase YES, particularly in CD24+ cells. Knockdown of Yes abolished the effects of Lkb1 loss on migration and invasion, led to a 7-fold decrease in metastasis of Lkb1-deficient tail-vein injected cells, and suppressed the expansion of the CD24+ population. Together, these data establish a role for LKB1 inactivation in melanomagenesis and metastasis and suggest that the development of YES-specific kinase inhibitors may be warranted for the treatment of LKB1-deficient melanomas.