Abstract P28: Metastatic Capabilities in Breast Cancer Cells are Potentiated by Resistance Against Membrane Damage Through Dysregulated Membrane Phospholipid Profiles and Annexin-Mediated Repair

Abstract

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 such tremendous biophysical 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 possessed dysregulated membrane phospholipid profiles and differential recruitment of key membrane repair proteins like Annexin A1 (ANXA1). The dysregulation of key abundant 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. When subjected to membrane physical and chemical perturbations, breast cancer cells of higher metastatic propensity experienced better survival outcomes, a phenomenon reversible by phenothiazine sensitisation by targeting ANXA1 and ANXA2 through charged membrane phospholipids.