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Head and neck squamous cell carcinoma (SCC) is a common worldwide cancer that is prone to metastasis characterized by tumor cell invasion and dissemination. Each metastatic lesion development decreases the patient survival rate by half. Recent studies have demonstrated that a subpopulation of tumor keratinocytes, spatially restricted to the leading edge of the tumor, exhibit a distinct partial epithelial-to-mesenchymal transition (pEMT) phenotype associated with tumor cell invasion, poorer prognosis and increased rates of metastasis. Previous evidence has shown that TGF-beta signaling promotes pEMT in SCC keratinocytes, yet a substantial proportion of SCC tumors harbor mutations in this pathway leading to absence of canonical TGF-beta response, as determined by phosphorylated SMAD3. To address this conundrum in the field we examined pEMT responses in primary head and neck SCC …