Produção Nacional
Revisado por pares
Abstract 431: ErbB4 is a novel driver of metastasis and anoikis resistance in Ewing's sarcoma
2012; American Association for Cancer Research; Volume: 72; Issue: 8_Supplement Linguagem: Inglês
10.1158/1538-7445.am2012-431
ISSN1538-7445
AutoresAriadna Mendoza‐Naranjo, Daniel Wai, Jason E. Farrar, Qingsong Zhu, Priti Mistry, Nikola Lazic, Fernanda Rocha Rojas Ayala, Isabela Werneck da Cunha, R.J. Arceci, Fernando Augusto Soares, Timothy J. Triche, Sandra J. Strauss, Poul H. Sorensen,
Tópico(s)CAR-T cell therapy research
ResumoAbstract Most Ewing family tumor (EFT) related deaths occur as a consequence of metastatic disease. Using high-throughput Affymetrix arrays, and matched primary and metastatic tumor-derived cell line pairs, we have identified ERBB4, a member of the epidermal growth factor receptor (EGFR) family, as a novel driver of metastasis and anoikis resistance in EFTs. Gene expression profiling, mRNA analysis, and immunoblotting revealed a 2 to 4-fold increase in ERBB4 expression in metastatic compared to primary EFT cell lines. SNP profiling failed to show copy number aberrations to explain the increased ErbB4 expression in metastatic cell lines. However, epigenetic mechanisms were found to potentially regulate ERBB4 expression in the paired CHLA-9 primary and in the metastatic/chemoresistant CHLA-10 cell line derived from the same patient. Treatment with 5-aza-2α-deoxycytidine enhanced ErbB4 in CHLA-9 cells, but reduced its expression in CHLA-10, suggesting a potential role for DNA methylation in controlling ERBB4 expression in EFTs. Enhanced protein expression and ErbB4 tyrosine kinase activation were clearly identified in metastatic versus primary cells grown under anchorage independent conditions (as multicellular spheroids), which mimic micrometastases. We next evaluated the clinical relevance of these data using biopsies from EFT patients. We found a direct correlation between ErbB4 expression and reduced disease-free survival (p<0.05), and identified statistically higher ErbB4 expression (p<0.05) in metastatic vs. primary biopsies (80% vs. 56%, respectively). ErbB4 gene knockdown or treatment with the FDA-approved pan-ErbB inhibitor Lapatinib reduced proliferation, blocked cell migration and tumor invasion, and sensitized metastatic/chemoresistant cell lines to EFT standard of care chemotherapeutic drugs. Taken together, our findings identify ErbB4 as a novel driver of metastasis in EFTs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 431. doi:1538-7445.AM2012-431
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