Resistance to Membrane Damage Enhances Metastatic Potential of Breast Cancer Cells via Dysregulated Phospholipid Profiles and Annexin-Mediated Repair

During cancer metastasis, invading cancer cells are required to navigate through various biophysical barriers. In the process of intravasation, circulation and extravasation, cancer cells which successfully overcome and survive these tremendous biophysical stressors can establish themselves as circulating tumour cell (CTC) precursors to secondary metastatic niches. Although metastatic processes have been well described by current literatures, the determining characteristics for invading cancer cells to withstand these stressors in the tumour microenvironment, remains poorly understood. Using isogenic breast cancer cells of varying metastatic propensities, we demonstrate that breast cancer cells of increasing metastatic propensity possess dysregulated membrane phospholipid profiles and differential recruitment of key membrane repair proteins like Annexin A1 (ANXA1). The dysregulation of key membrane structural phospholipids like phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin (SM) influences membrane structure and integrity. Cumulatively, our investigation revealed that breast cancer cells with higher metastatic potential possessed greater PC/PE ratio, indicative of an enhanced membrane integrity. The simultaneous upregulation of membrane repair calcium-dependent phospholipid-binding ANXA1 and ANXA2 suggests an interplay between membrane repair and phospholipid dysregulation in governing its membrane integrity and subsequent resistance against damage. These findings identify membrane lipid remodelling and annexin-mediated repair as coupled processes that confer metastatic breast cancer cells with resistance to membrane damage, highlighting therapeutic vulnerabilities which could be exploited.