ETV5 transcription program links BDNF and promotion of EMT at invasive front of endometrial carcinomas

Abstract

Myometrial infiltration represents a main clinical determinant of endometrial carcinomas (EC) presenting as aggressive high-grade deeply invasive neoplasms, substantially associated with risk of recurrence and death. The up-regulation of ETV5 transcription factor linked to the promotion of epithelial to mesenchymal transition is considered as a basic mechanism underlying the initial steps of EC invasion. In this work, we aimed to investigate the transcription program of tumor invasion regulated by ETV5. We performed a comparative Chip-on-chip analysis at invasive front and superficial area of human EC. ETV5 specific binding to promoter regions of genes related to cellular migration, adhesion and invasion at deep invasion tumor areas highlighted the relevance of neural networks associated with cellular plasticity. Interestingly, brain-derived neurotrophic factor (BDNF) demonstrated a principal role orchestrating ETV5-mediated epithelial-to-mesenchymal transition in endometrial cancer. Impairment of the BDNF/tropomyosin-related kinase B (TrkB)/extracellular signal-regulated kinase axis in endometrial cancer cell lines reversed the aggressive and invasive phenotype promoted by the up-regulation of ETV5 at the invasive front of EC. Likewise, BDNF directly impacted on the efficiency of ETV5 promoted metastasis in a mice model of endometrial distant dissemination. These results translate the recognized role of BDNF/TrkB on neural plasticity into a relevant cancer metastasis event; suggest common mechanisms shared by neural development and tumor invasion; and offer new therapeutic opportunities specifically directed against disseminated disease in endometrial cancer.

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

“…Interestingly, BDNF demonstrated a principal role coordinating ETV5 mediated EMT in EC. Impairment of BDNF/TrkB/ERK axis in EC cells reversed the aggressive and invasive phenotype promoted by the upregulation of ETV5 at the invasive front (Alonso-Alconada et al 2014). ETV5 related proteomic approach performed in Hec1A cell line reinforced a role of this transcription factor in regulation of the migratory and invasive tumor behavior (Monge et al 2009).…”

Liver Metastasis Is Facilitated by the Adherence of Circulating Tumor Cells to Vascular Fibronectin Deposits

“…CT26 LifeAct-GFP and HCT116-Luc cells were generated by lentiviral infection as described previously (14). HCT116-Luc cells were selected using blasticidine HCl (10 mg/mL).…”

BDNF: An Oncogene or Tumor Suppressor?

“…What is of considerable interest is that the BDNF/TrkB pathway has been shown to mediate the resistance to anoikis of multiple cancers (9,18,(25)(26)(27)(28)(29). it was shown that in multiple cancers, metastatic tumor cells have up-regulated TrkB and BDNF compared to tumor cells that did not metastasize (18,26,29).…”