Epiregulin expression and the dual role of pro-inflammatory macrophages in the tumor microenvironment of Non-Small Cell Lung Carcinoma

Author(s)

Vinícius Jardim Carvalho

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Matemática e Estatística (IME/SBI)
• Defense date: 2023-05-11

Examining board members

André Fujita; Benilton de Sá Carvalho; Mariana Lima Boroni Martins; Eduardo Moraes Rego Reis

• Advisor: André Fujita; Gilberto de Castro Junior

Abstract

Lung cancer is the leading cause of cancer deaths worldwide. A better understanding of the processes involved in tumor progression is required, in addition to the search for biomarkers related to its degree of aggressiveness. The signal transduction pathway employing receptors with tyrosine kinase activity, such as the epidermal growth factor receptor (EGFR), is critical to neoplastic cell survival. Among the EGFR ligands is epiregulin (EREG). The literature points out that EREG is related to worse prognosis and resistance to treatment with tyrosine kinase inhibitors (TKI-EGFR). However, it is unclear in which contexts this expression occurs. Our objective was to investigate the relationship of EREG expression with survival in non-small cell lung cancer (NSCLC) patients and in which tumor contexts this expression occurs. Increased gene expression is strongly related to shorter overall survival in early-stage NSCLC patients. The prognostic impact of EREG expression was used to define the survival of new patients in independent databases. We also observed that macrophages are the cell type with the highest expression of EREG, mainly related to the pro-inflammatory phenotype (M1). Stimulation with EREG leads to prolonged phosphorylation of EGFR, which may be related to resistance to treatment with EGFR-TKIs in NSCLC. Another macrophage phenotype analyzed was tolerized. We saw that this phenotype expresses high values of EREG and pro-inflammatory cytokines. Cell proliferation analyses showed that the culture medium of the tolerized macrophage stimulates higher proliferation, which was not observed for the M1 macrophage. The tolerized macrophage allows us to explain the relationship between pro-inflammatory biomarkers and EREG in the tumor context. These results bring new evidence on the resistance to treatment with EGFR-TKIs by the paracrine pathway, suggesting further studies on therapies directed at EREG expression in tolerized macrophages. (AU)

• FAPESP's process: 19/03615-2 - Diffusion in directed networks in a triple-negative breast cancer study
• Grantee: Vinícius Jardim Carvalho
• Support Opportunities: Scholarships in Brazil - Doctorate