Stromal CXCL14 Promotes Cisplatin Resistance in Lung Adenocarcinoma by Activating ANGPTL4 Signaling Pathway

Abstract

Background: Cisplatin-based therapy remains a critical treatment for patients with advanced lung adenocarcinoma (LUAD). However, the development of resistance to cisplatin hampers the sustained benefit to patients. Recent studies have shown that molecules secreted by stromal tissue play a pivotal role in tumor chemoresistance. This study aimed to validate the role of CXC-chemokine ligand 14 (CXCL14), a stromal-secreted molecule, and its functional mechanism in cisplatin resistance. Methods: We analyzed The Cancer Genome Atlas (TCGA) database using bioinformatics methods, leading to the selection of CXCL14 for validation on a LUAD tissue microarray (TMA) of 120 patients. The protein expression of CXCL14 was assessed through immunohistochemistry (IHC). A549 and H3255 cells were cultured in two-dimensional (2D) or three-dimensional (3D) patterns. In this study, we evaluated cell viability, cell apoptosis and death, molecular expression, signaling pathways, and xenograft growth using in vitro methods such as Cell Counting Kit-8 (CCK8) assays, colony formation assays, flow cytometry, cell live/dead double staining, quantitative PCR, Western blot, RNA sequencing, and in vivo mouse tumor-bearing models. Results: CXCL14 was found to be highly expressed in the stroma of lung adenocarcinoma in both the TCGA training cohort and the TMA validation cohort, suggesting its potential role in the interaction between stromal and tumor cells. Cisplatin inhibited cell viability, induced cell apoptosis in 2D or 3D cultured A549 and H3255 cells in vitro, and suppressed tumor growth in vivo. These effects were significantly alleviated by adding CXCL14. Further investigation revealed that CXCL14 promoted cisplatin resistance by upregulating Angiopoietin Like Protein 4 (ANGPTL4), activating the downstream extracellular regulated protein kinases (ERK) signaling pathways. Conclusion: CXCL14, a stromal marker, promotes cisplatin resistance in LUAD by activating ANGPTL4 and the downstream ERK signaling pathway. Identifying the downstream effectors, or the use of neutralizing/non-neutralizing antibodies targeting this pathway may provide valuable insights and serve as a reference for developing strategies to effectively control cisplatin resistance, a topic that warrants further investigation.