Tumor cell intrinsic Toll-like receptor 4 signaling promotes melanoma progression and metastatic dissemination

Most melanoma-associated deaths result from the early development of metastasis. Toll-like receptor 4 (TLR4) expression on nontumor cells is well known to contribute to tumor development and metastatic progression. The role of TLR4 expression on tumor cells however is less well understood. Here we describe TLR4 as a driver of tumor progression and metastatic spread of melanoma cells by employing a transplantable mouse melanoma model. HCmel12 melanoma cells lacking functional TLR4 showed increased sensitivity to tumor necrosis factor alpha induced cell killing in vitro compared to cells with intact TLR4. Interestingly, TLR4 knockout melanoma cells also showed impaired migratory capacity in vitro and a significantly reduced ability to metastasize to the lungs after subcutaneous transplantation in vivo. Finally, we demonstrate that activation of TLR4 also promotes migration in a subset of human melanoma cell lines. Our work describes TLR4 as an important mediator of melanoma migration and metastasis and provides a rationale for therapeutic inhibition of TLR4 in melanoma.