An integrated platform for dual-responsive circulating tumor cells release and lipidomics revealing predictive metabolic signatures of breast cancer lung metastasis.

BACKGROUND

Breast cancer metastasis remains a leading cause of mortality, involving the dissemination of circulating tumor cells (CTCs) through the bloodstream. Lipid metabolic reprogramming not only fuels cancer cells but also regulates CTC survival and colonization by coordinating systemic metabolic adaptation across primary tumors, circulation, and target organs. However, the lack of methods for simultaneously isolating viable CTCs and performing multidimensional lipidomic profiling has hindered direct experimental evidence linking CTC dynamics to systemic lipid reprogramming.

RESULTS

To address this, an integrated "CTC-multidimensional lipidomics" platform was developed. The system incorporates a dual-responsive nanomaterial (Fe3O4@PEI‑Cys‑HA) with untargeted lipidomics, enabling synchronous high‑fidelity sampling and multidimensional analysis of CTCs, primary tumors, plasma, and lung metastases in a breast cancer lung metastasis model. The nanomaterial achieves > 80% capture efficiency and > 80% high-viability release through hyaluronic acid-mediated targeting and HAase/DTT-triggered dual responses. Integrated lipidomics revealed that CTC dissemination correlates with systemic lipid alterations, with key lipids (e.g., PI 36:2) showing coordinated spatiotemporal patterns. These findings support a three-stage "coordinated lipid reprogramming" framework linking lipid metabolism to CTC shedding, survival, and colonization.

SIGNIFICANCE: By enabling synchronized tracking of CTC dynamics and associated lipid alterations, this work provides a novel analytical platform for investigating the CTC-lipid metabolism axis. Beyond serving as a versatile CTC analysis tool, this study highlights the predictive value of lipids in metastasis and offers a new perspective for tumor dissemination research.