Co-Overexpression of TWIST1-CSF1 Is a Common Event in Metastatic Oral Cancer and Drives Biologically Aggressive Phenotype

Autor(es):Mostrar menos -

da Silva, Sabrina Daniela ^{[1, 2, 3, 4]} ; Marchi, Fabio Albuquerque ^{[5, 6]} ; Su, Jie ^{[2, 3, 4]} ; Yang, Long ^[7] ; Valverde, Ludmila ^[1] ; Hier, Jessica ^[1] ; Bijian, Krikor ^{[2, 3, 4]} ; Hier, Michael ^[1] ; Mlynarek, Alex ^[1] ; Kowalski, Luiz Paulo ^{[5, 6]} ; Alaoui-Jamali, Moulay A. ^{[2, 3, 4]}

Afiliação do(s) autor(es)

^[1] Sir Mortimer B Davis Jewish Hosp, Dept Otolaryngol Head & Neck Surg, Montreal, PQ H3T 1E2 - Canada

^[2] McGill Univ, Sir Mortimer B Davis Jewish Gen Hosp, Fac Med, Segal Canc Ctr & Lady Davis Inst Med Res, Dept Med, Montreal, PQ H3T 1E2 - Canada

^[3] McGill Univ, Sir Mortimer B Davis Jewish Gen Hosp, Fac Med, Dept Oncol, Segal Canc Ctr & Lady Davis Inst Med Res, Montreal, PQ H3T 1E2 - Canada

^[4] McGill Univ, Sir Mortimer B Davis Jewish Gen Hosp, Fac Med, Dept Pharmacol & Therapeut, Segal Canc Ctr & Lady Davis Inst Med Res, Montreal, PQ H3T 1E2 - Canada

^[5] Natl Inst Sci & Technol Oncogen INCITO, BR-01509010 Sao Paulo - Brazil

^[6] AC Camargo Canc Ctr, Dept Head & Neck Surg & Otorhinolaryngol, BR-01509010 Sao Paulo - Brazil

^[7] Tianjin Univ Tradit Chinese Med, Sch Integrat Med, Tianjin 301617 - Peoples R China

• Tipo de documento: Artigo Científico
• Fonte: CANCERS; v. 13, n. 1 JAN 2021.
• Citações Web of Science: 0

Resumo

Simple Summary There is clinical evidence that ulcerated and inflammatory cell-infiltrated oral cancer is frequently associated with early metastases. Our results from genomic screening in patients with metastatic oral cancer identified specific changes in genes that regulate macrophage chemotaxis and drive tumor progression. This opens up potential therapeutic opportunities toward personalized medicine tailored to manage patients with advanced disease. Invasive oral squamous cell carcinoma (OSCC) is often ulcerated and heavily infiltrated by pro-inflammatory cells. We conducted a genome-wide profiling of tissues from OSCC patients (early versus advanced stages) with 10 years follow-up. Co-amplification and co-overexpression of TWIST1, a transcriptional activator of epithelial-mesenchymal-transition (EMT), and colony-stimulating factor-1 (CSF1), a major chemotactic agent for tumor-associated macrophages (TAMs), were observed in metastatic OSCC cases. The overexpression of these markers strongly predicted poor patient survival (log-rank test, p = 0.0035 and p = 0.0219). Protein analysis confirmed the enhanced expression of TWIST1 and CSF1 in metastatic tissues. In preclinical models using OSCC cell lines, macrophages, and an in vivo matrigel plug assay, we demonstrated that TWIST1 gene overexpression induces the activation of CSF1 while TWIST1 gene silencing down-regulates CSF1 preventing OSCC invasion. Furthermore, excessive macrophage activation and polarization was observed in co-culture system involving OSCC cells overexpressing TWIST1. In summary, this study provides insight into the cooperation between TWIST1 transcription factor and CSF1 to promote OSCC invasiveness and opens up the potential therapeutic utility of currently developed antibodies and small molecules targeting cancer-associated macrophages. (AU)

• Processo FAPESP: 08/57887-9 - Instituto Nacional de Oncogenômica
• Beneficiário: Luiz Paulo Kowalski
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 06/61039-8 - Identificacao de marcadores moleculares de progressao e prognostico em carcinomas epidermoides de boca.
• Beneficiário: Luiz Paulo Kowalski
• Modalidade de apoio: Auxílio à Pesquisa - Regular