SEMA3C regulates tumor-associated macrophage phenotype and influences lung cancer cell migration and invasion through VNN1.

Abstract

ObjectiveTo investigate the mechanism of tumor-associated macrophages (TAM) in the invasive migration of lung adenocarcinoma (LUAD) cells.MethodsThe single-cell sequencing data of lung adenocarcinoma (GSE131907) were initially analyzed. Kaplan-Meier curve analysis, univariate as well as multivariate Cox analysis, and immunofluorescence staining were performed. The analysis of fibroblast-macrophage interactions using Single-cell CellChat revealed their relationship. Subsequently, we screened and validated the target proteins in macrophages that interact with SEMA3C. The effects of these interactions on lung cancer cell migration and invasion were evaluated in vitro through Western blot analysis to assess phenotypic changes in macrophages, as well as through Transwell migration and invasion assays.ResultsSEMA3C was predominantly expressed in fibroblasts of patients with high-grade lung adenocarcinoma at high levels. SEMA3C exhibited independent prognostic significance in determining the overall survival outcome among individuals diagnosed with lung adenocarcinoma. Lung adenocarcinoma fibroblasts had elevated SEMA3C. CellChat demonstrated enhanced interactions between TAM as well as T cells. A high expression of vascular non-inflammatory molecule 1 (VNN1) in fibroblast macrophages during Stage II-III, and this elevated VNN1 was also an independent prognostic factor. The interaction between cancer-associated fibroblasts (CAFs) and VNN1 on macrophage membranes mediated by SEMA3C. Furthermore, these experiments demonstrated that SEMA3C regulates the polarization of TAM through VNN1, thereby influencing lung cancer.ConclusionThe phenotype of TAM is regulated by SEMA3C, which in turn influences the migration as well as invasion of lung cancer cells through VNN1.