STK11 Prevents Invasion Through STAT3/5 and FAK Repression in Cutaneous Melanoma

The serine/threonine kinase 11 (STK11/LKB1) is a tumor suppressor involved in metabolism and cell motility. In BRAFV600E melanoma, STK11 is inactivated by ERK and RSK, preventing it from binding and activating AMPK and promoting melanoma cell proliferation. Although STK11 mutations occur in 5-10% of cutaneous melanoma, few functional studies have been performed. By knocking out STK11 with CRISPR/Cas9 in two human BRAF-mutant melanoma cell lines, we found that STK11-loss reduced the sensitivity to a BRAF inhibitor (BRAFi). More strikingly, STK11 loss led to an increased invasive phenotype in both 3-dimensional spheroids and in vivo zebrafish xenograft models. STK11 overexpression consistently reverted the invasive phenotype. Interestingly, STK11 knockout increased invasion also in an NRAS-mutant melanoma cell line. Furthermore, while STK11 was expressed in primary human melanoma tumors, its expression significantly decreased in melanoma metastases especially in brain metastases. In the STK11-knockout cells we observed increased activating phosphorylation of STAT3/5 and FAK. Using inhibitors of STAT3/5 and FAK, we reverted the invasive phenotype in both BRAF and NRAS mutated cells. Our findings confirm an increased invasive phenotype upon STK11-inactivation in BRAF and NRAS-mutant cutaneous melanoma that can be targeted by STAT3/5 and FAK-inhibition.