BDNF/TRKB axis provokes EMT progression to induce cell aggressiveness via crosstalk with cancer-associated fibroblasts in human parotid gland cancer

• Published in: Scientific reports Vol. 12; no. 1; p. 17553
• Main Authors: Moriwaki, Kazumasa, Wada, Masaki, Kuwabara, Hiroko, Ayani, Yusuke, Terada, Tetsuya, Higashino, Masaaki, Kawata, Ryo, Asahi, Michio
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 20.10.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cancer; Cancer-Associated Fibroblasts - metabolism; Cell culture; Cell Line, Tumor; Cell migration; Culture Media, Conditioned; Epithelial-Mesenchymal Transition; Exocrine glands; Fibroblasts; Humans; Invasiveness; Malignancy; Mesenchyme; Metastases; Oral cancer; Parotid gland; Parotid Gland - metabolism; Patients; Prognosis; Receptor, trkB - metabolism; Salivary Gland Neoplasms - metabolism; Salivary Gland Neoplasms - pathology; Stromal cells; Therapeutic targets; TrkB receptors; Tropomyosin; Tumor cells
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-22377-9

Parotid gland cancer (PGC) is a rare malignancy and its molecular characteristics remain poorly understood, which has precluded the development of effective drug therapies. Given the poor prognosis of many human cancers in which tropomyosin receptor kinase B (TRKB) is highly expressed, we investigated the involvement of brain-derived neurotrophic factor (BDNF)/TRKB pathway in PGC cells using clinical specimens and observed upregulation of TRKB and BDNF. In primary culture systems of patient-derived PGC cells and cancer-associated fibroblasts (CAFs), PGC cells co-cultured with CAFs exhibited significant upregulation of BDNF and epithelial-mesenchymal transition (EMT). Similar results were observed in PGC cells treated with conditioned medium from co-cultures of PGC cells with CAFs. Administration of TRK inhibitors suppressed BDNF-induced cell migration in PGC cells. Immunohistochemical and clinicopathological analyses of tumors from patients with PGC revealed that BDNF and TRKB were highly expressed in both tumor cells and stromal cells such as CAFs, and TRKB expression levels in PGC cells were significantly correlated with aggressive features, including vascular invasion, nodal metastasis, and poor prognosis. Collectively, these data suggest that the BDNF/TRKB pathway regulates PGC cell aggressiveness via crosstalk with CAFs and is a potential therapeutic target for PGC harboring invasive and metastatic features.