BRAF inhibitor-resistant melanoma promotes CXCL1 expression to recruit cancer-associated fibroblasts
10.12025/j.issn.1008-6358.2026.20261050
- VernacularTitle:BRAF抑制剂耐药黑素瘤促进CXCL1表达招募肿瘤相关成纤维细胞
- Author:
Yiteng DING
1
;
Lilu XIE
1
;
Tianyi ZHANG
1
;
Chuanyuan WEI
1
;
Jianying GU
1
Author Information
1. Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
- Publication Type:Originalarticle
- Keywords:
melanoma;
BRAF inhibitor;
targeted therapy;
cancer-associated fibroblast;
CXCL1
- From:
Chinese Journal of Clinical Medicine
2026;33(5):807-818
- CountryChina
- Language:Chinese
-
Abstract:
Objective To explore the key molecule and signaling pathway involved in the recruitment of cancer-associated fibroblasts (CAFs) by BRAF inhibitor (BRAFi)-resistant melanoma. Methods Tumor tissue sections were collected from 20 melanoma patients who received BRAFi-targeted therapy in Zhongshan Hospital, Fudan University, between September 2024 and September 2025, including 10 cases in the BRAFi-resistant group and 10 cases in the BRAFi-sensitive group. Immunohistochemical staining was performed to compare the number of CAFs in tumor tissues in the two groups. A co-culture model was established to compare the half-maximal inhibitory concentration (IC50) of BRAFi in melanoma cells under co-culture conditions with CAFs versus non-co-culture conditions. Differential gene expression between BRAFi-sensitive and BRAFi-resistant melanoma was analyzed using publicly available sequencing data (GSE196434), and key differentially expressed genes were identified. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were employed to validate the expression differences of CXCL1 between BRAFi-sensitive and BRAFi-resistant melanoma cells, and to detect CXCL1 expression in melanoma cells treated or untreated with the AKT inhibitor (AKTi). Transwell invasion assays were performed to evaluate the recruitment capability of BRAFi-resistant and BRAFi-sensitive melanoma cells toward CAFs, and to compare the differences in recruitment capability of melanoma cells toward CAFs among the AKTi-treated group, the AKTi＋CXCL1-treated group, and the control group. Results The number of CAFs was significantly higher in the BRAFi-resistant group than that in the BRAFi-sensitive group (P＜0.01). The cell viability (P＜0.01) and IC50 were higher in the melanoma co-culture group with CAFs than in the non-co-culture group. CXCL1 was identified as a key differentially expressed gene, with higher expression in BRAFi-resistant melanoma than in BRAFi-sensitive melanoma (P＜0.01). AKTi treatment suppressed CXCL1 expression in BRAFi-resistant melanoma (P＜0.01). BRAFi-resistant melanoma exhibited a stronger CAF-recruiting capacity than BRAFi-sensitive melanoma (P＜0.05), and AKTi treatment reduced its ability to recruit CAFs (P＜0.05). This effect was restored after the addition of exogenous CXCL1 (P＜0.05). Conclusions BRAFi-resistant melanoma activates the AKT pathway to upregulate CXCL1, thereby recruiting CAFs.
