Podoplanin drives amoeboid invasion in canine and human mucosal melanoma.

Mucosal melanoma metastasizes at an early stage of the disease in human and dog. We revealed that overexpression of podoplanin (PDPN) in tumor invasion fronts (IFs) was related to poor prognosis of dogs with mucosal melanoma. Moreover, PDPN expressed in canine mucosal melanoma cells promotes proliferation and aggressive amoeboid invasion by activating Rho-associated kinase (ROCK)-myosin light chain 2 (MLC2) signaling. PDPN-ROCK-MLC2 signaling plays a role in cell cycle arrest and cellular senescence escape as a mechanism for regulating proliferation. PDPN induces amoeboid invasion in the IFs of mouse xenografted tumor tissues, similar to canine mucosal melanoma clinical samples. We further identified that PDPN expression was related to poor prognosis of human patients with mucosal melanoma, and human mucosal melanoma with PDPN high expression enriched gene signatures related to amoeboid invasion, similar to canine mucosal melanoma. Overall, we propose that PDPN promotes canine and human mucosal melanoma metastasis by inducing aggressive amoeboid invasion and naturally occurring canine mucosal melanoma can be a novel research model for PDPN expressing human mucosal melanoma. Implications: PDPN could be a new therapeutic target to restrict the metastatic dissemination of canine and human mucosal melanoma.