CAFs mediate carboplatin resistance in LUAD via CXCL12 secretion regulated by NF-κB activation.

Abstract

Purpose: Cancer-associated fibroblasts (CAFs) are major constituents of the tumor microenvironment (TME) and have been associated with chemotherapeutic failure via different mechanisms. However, the CAFs inhibit chemotherapy mechanism in lung adenocarcinoma (LUAD) remains undetermined.

Methods: Fibroblasts were isolated from tumor and normal lung tissues from patients with poorly differentiated LUAD (pCAFs), moderately differentiated LUAD (mCAFs), and normal fibroblasts (NFs). Then, the influence of these fibroblasts on carboplatin's cytotoxic effects on LUAD cell lines A549 and NCI-H1299 was assessed by measuring their IC₅₀ values. Furthermore, CXCL12 secretion and its role in chemotherapeutics were also evaluated.

Results: The data revealed that pCAFs significantly inhibited apoptosis in LUAD cells and increased carboplatin IC₅₀ values. Furthermore, pCAFs secreted higher CXCL12 content than mCAFs and NFs. Moreover, in pCAFs, CXCL12 silencing enhanced carboplatin's cytotoxic effects, while NFs overexpressing CXCL12 inhibited carboplatin's efficacy. Mechanistically, pCAFs promote the secretion of CXCL12 by activating the NF-κB pathway, and CXCL12 binds to CXCR4 on LUAD cells, thereby promoting carboplatin resistance. Moreover, in the xenograft models, pCAFs were found to reduce carboplatin's cytotoxicity by CXCL12 secretion. Moreover, the analysis of the LUAD patient's tumor and peripheral blood sample indicated a correlation between lower differentiation and higher CXCL12 expression levels.

Conclusion: This study revealed that LUAD-derived CAFs activate the NF-κB axis to secrete CXCL12, thereby weakening the carboplatin's killing effect on LUAD. Furthermore, poorly differentiated LUAD secreted more CXCL12. These findings indicate a novel strategy to enhance carboplatin's chemotherapeutic potential against LUAD.