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TrkB-Targeted Therapy for Mucoepidermoid Carcinoma.

ABSTRACT: The brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (TrkB) pathway was previously associated with key oncogenic outcomes in a number of adenocarcinomas. The aim of our study was to determine the role of this pathway in mucoepidermoid carcinoma (MEC). Three MEC cell lines (UM-HMC-2, H253 and H292) were exposed to Cisplatin, the TrkB inhibitor, ANA-12 and a combination of these drugs. Ultrastructural changes were assessed through transmission electron microscopy; scratch and Transwell assays were used to assess migration and invasion; and a clonogenic assay and spheroid-forming assay allowed assessment of survival and percentage of cancer stem cells (CSC). Changes in cell ultrastructure demonstrated Cisplatin cytotoxicity, while the effects of ANA-12 were less pronounced. Both drugs, used individually and in combination, delayed MEC cell migration, invasion and survival. ANA-12 significantly reduced the number of CSC, but the Cisplatin effect was greater, almost eliminating this cell population in all MEC cell lines. Interestingly, the spheroid forming capacity recovered, following the combination therapy, as compared to Cisplatin alone. Our studies allowed us to conclude that the TrkB inhibition, efficiently impaired MEC cell migration, invasion and survival in vitro, however, the decrease in CSC number, following the combined treatment of ANA-12 and Cisplatin, was less than that seen with Cisplatin alone; this represents a limiting factor.

SUBMITTER: Wagner VP

PROVIDER: S-EPMC7759804 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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TrkB-Targeted Therapy for Mucoepidermoid Carcinoma.

Wagner Vivian P VP Martins Manoela D MD Amoura Esra E Zanella Virgilio G VG Roesler Rafael R de Farias Caroline B CB Bingle Colin D CD Vargas Pablo A PA Bingle Lynne L

Biomedicines 20201124 12

The brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (TrkB) pathway was previously associated with key oncogenic outcomes in a number of adenocarcinomas. The aim of our study was to determine the role of this pathway in mucoepidermoid carcinoma (MEC). Three MEC cell lines (UM-HMC-2, H253 and H292) were exposed to Cisplatin, the TrkB inhibitor, ANA-12 and a combination of these drugs. Ultrastructural changes were assessed through transmission electron microscopy; scratch and Tr ...[more]

PMID: 33255325

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Project description:BackgroundPrimary pancreatic mucoepidermoid carcinoma (MEC) is an extremely rare malignant tumor with unclear etiology and pathogenesis. There are only eleven reported cases in English papers published from 1959 to 2020. MEC generally occurs in the salivary gland, but cases in the pancreas have also been reported. Although being considered as a low-grade indolent carcinoma, pancreatic MEC always invades the surrounding lymph node and metastasizes. The prognosis of pancreatic MEC is unsatisfactory. To date, the genetic alterations, mechanistic relationships among mutated genes and signaling pathways of pancreatic MEC are unclear.Patient and methodsThis paper presents a case of rare primary pancreatic MEC in a 56-year-old male patient with liver metastasis. Radical surgery of distal pancreatectomy and radiofrequency ablation (RFA) of two liver metastatic lesions is conducted. Targeted-gene sequencing and bioinformatics analysis tools, including STRING, DAVID, cBioPortal, DGidb and Human Protein Atlas database (HPA), are used to clarify the biological functions and features of mutated genes in pancreatic MEC.ResultsEight gene mutations (TP53, KRAS, ATR, FLI1, FLT4, MAGI2, RBM10, and TNFAIP3) were observed, and a tumor mutation burden (TMB) of 5.6 muts/Mb was calculated in the pancreatic MEC using targeted-gene sequencing. The patient subsequently underwent adjuvant chemotherapy and died three months after surgery. Gene-gene interaction network was constructed, which showed the significant interactions among eight mutated genes. In terms of the functions and pathways of eight gene mutations based on GO and KEGG, 20 tumor-related results are presented in this paper, Furthermore, the biological functions and features of pancreatic MEC are further compared with pancreatic ductal adenocarcinoma.ConclusionPancreatic MEC requires early and effective treatment, and lymph node metastases and multiple organ metastases were unfavorable prognostic factors. Pancreatic MEC can be compared with other pancreatic cancers that have characteristic clinical phenotype, molecular alterations, functional information and enrichment pathway.

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TrkB-Targeted Therapy for Mucoepidermoid Carcinoma.

Publications

TrkB-Targeted Therapy for Mucoepidermoid Carcinoma.

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