TSPAN1: A Novel Protein Involved in Head and Neck Squamous Cell Carcinoma Chemoresistance

SIMPLE SUMMARY: Therapy resistance in head and neck squamous cell carcinoma (HNSCC) patients is the main obstacle to achieve more effective treatments that improve survival and quality of life of these patients. Therefore, it is of vital importance to unravel the molecular and cellular mechanisms by which tumor cells acquire resistance to chemotherapy. We conducted a comparative proteomic study involving cisplatin-resistant cells and cancer stem cells with the aim of identifying proteins potentially implicated in the acquisition of cisplatin resistance. Through this study, we identified for the first time tetraspanin-1 (TSPAN1) as an important protein involved in the development, progression and chemoresistance of HNSCC tumors. ABSTRACT: Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. A proteomic study revealed tetraspanin-1 (TSPAN1) as a protein involved in acquisition of cisplatin (CDDP) resistance (Data are available via ProteomeXchange with identifier PXD020159). TSPAN1 was found to increase in CDDP-resistant cells, CSCs and biopsies from head and neck squamous cell carcinoma (HNSCC) patients. TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target. Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading. Notably, CDDP-resistant tumors showed epithelial–mesenchymal transition (EMT) features that disappeared upon TSPAN1 inhibition, suggesting a link of TSPAN1 with EMT and metastasis. Immunohistochemical analysis of HNSCC specimens further revealed that TSPAN1 expression was correlated with phospho-SRC (pSRC), and inversely with E-cadherin, thus reinforcing TSPAN1 association with EMT. Overall, TSPAN1 emerges as a novel oncogenic protein and a promising target for HNSCC therapy.