Proteomics and Lipidomics Analysis Reveal That Membrane Remodeling and Extracellular Matrix Alterations Are Crucial for Cisplatin Resistance in Triple-Negative Breast Cancer

Cisplatin is a widely used chemotherapeutic agent for
triple-negative
breast cancer (TNBC), but resistance remains a major challenge. Understanding
the molecular alterations driving this resistance is essential for
identifying therapeutic targets. In this study, we employed an integrated
proteomics and lipidomics approach to elucidate key pathways associated
with cisplatin resistance. Employing high-resolution mass spectrometry,
we conducted a comparative analysis between cisplatin-resistant (cisR)
and cisplatin-sensitive (cisS) TNBC cell lines to discover resistance-associated
alterations in protein and lipid expression. Proteomic analysis revealed
overexpression of extracellular matrix (ECM) remodeling proteins,
COL6A1, COL6A2, COL6A3, and VTN, that support epithelial-mesenchymal
transition (EMT) and chemoresistance. Membrane-associated proteins
such as TIMP2, MMP14, and APP were also elevated, indicating enhanced
invasive and pro-survival signaling. Lipidomic alterations, including
upregulation of FABP3, FABP4, LPL, and downregulation of PLA2G4A,
indicated increased lipid uptake, metabolic rewiring, and membrane
restructuring. Notably, elevated long-chain phosphatidylcholines and
decreased sphingomyelins suggested increased membrane rigidity and
reduced cisplatin permeability. Additionally, dysregulation of CDK
activity through CCND2, CCND3, and CCNB2 overexpression indicated
accelerated cell cycle progression and evasion of DNA damage checkpoints.
Together, this integrative analysis highlights ECM remodeling, cytoskeletal
dynamics, and lipid metabolism as major contributors to cisplatin
resistance and identifies potential therapeutic markers for TNBC.