Lysosomal acid lipase-activity as a novel target to efficiently address triple-negative breast cancer high malignancy

Abstract

AbstractIncreased metabolism of neutral lipids, e.g. triglycerides and cholesterol esters, is a hallmark of malignant cancers such as triple-negative breast cancer (TNBC). Predominantly, cancer cells with a high epigenetic stem cell-associated signature increasingly utilize neutral lipids to maintain their high degree of tumor stemness, linking metabolic aberrations to epigenetically dysregulated differentiation processes. Lysosomal acid lipase (LIPA) is a central enzyme in the cellular utilization of exogenous and endogenous neutral lipids; however, the role of LIPA-activity in TNBC remains unexplored. We here show for the first time that pharmacological inhibition of LIPA, highly expressed in TNBC, reduces the expression markers of breast cancer stemness in cell culture models of TNBC. A role of LIPA in maintaining TNBC high cellular stemness was stressed by specific siRNA knock-down. Furthermore, inhibition of LIPA sensitized TNBC cells to therapy with Paclitaxel and Doxorubicin, two important chemotherapeutics in current TNBC treatment. When LIPA-activity was inhibited in a three-dinensional (3D) patient derived organoid model, we observed a significant reduction in TNBC cellular viability. Importantly, LIPA inhibition prevented tumor metastasis in a TNBC-zebrafish xenograft modelin vivo. These findings introduce LIPA-activity as a novel pharmacological target in TNBC therapy to specifically address its high cancer malignancy with a potential for implementation of LIPA inhibitors into personalized treatment in the future.