Podoplanin Drives Amoeboid Invasion in Canine and Human Mucosal Melanoma

Abstract

AbstractMucosal melanoma metastasizes at an early stage of the disease in human and dog. We revealed that overexpression of podoplanin in tumor invasion fronts (IF) was related to poor prognosis of dogs with mucosal melanoma. Moreover, podoplanin 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. Podoplanin induces amoeboid invasion in the IFs of mouse xenografted tumor tissues, similar to canine mucosal melanoma clinical samples. We further identified that podoplanin expression was related to poor prognosis of human patients with mucosal melanoma, and human mucosal melanoma with podoplanin-high expression enriched gene signatures related to amoeboid invasion, similar to canine mucosal melanoma. Overall, we propose that podoplanin 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 podoplanin expressing human mucosal melanoma.Implications:Podoplanin could be a new therapeutic target to restrict the metastatic dissemination of canine and human mucosal melanoma.