Project Details
Projekt
Lipid droplet heterogeneity in cancer proliferation and stress resistance
Subject Area
Cell Biology
Biochemistry
Hematology, Oncology
Biochemistry
Hematology, Oncology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 538651361
Lipid droplets (LDs) are dynamic organelles that play vital roles in the control of cellular lipid metabolism. Their specific lipid and protein composition is highly heterogenous and can change rapidly in response to altered nutrient availability and cellular metabolic state. Cancer cells induce LD formation in response to the activation of different oncogenic signaling pathways or changes in nutrient and oxygen availability in the tumor microenvironment. LD heterogeneity, as defined by differences in molecular composition, number, localization and appearance, contributes to their dynamic function in controlling cellular bioenergetics and stress response. Specifically, LDs protect cancer cells from ferroptosis, an iron-mediated form of cell death induced by excess lipid peroxidation, by sequestering poly-unsaturated fatty acids (PUFA) to protect them from oxidative damage. In addition, LDs provide a reservoir for mono-unsaturated fatty acids (MUFA) that counteract lipid peroxidation. Targeting of different fatty acids to LDs is controlled by a group of enzymes that selectively catalyse the activation and coupling of different fatty acids during triglyceride synthesis and several of these enzymes are deregulated in cancer. The aim of the proposed project is to investigate the role of enzymes that control fatty acid channeling and LD diversification in promoting cellular bioenergetics, oxidative stress resistance and oncogenic signaling in cancer cells. We will investigate expression and subcellular localization of the different factors that govern fatty acid channeling and LD heterogeneity in liver cancer, using established cell lines and animal models. We will determine the impact of different oncogenic drivers and tumor-like environmental constraints on LD heterogeneity. We will also investigate the consequences of modulating the activity of these factors on cellular lipid composition and LD heterogeneity in cancer cells. Specifically, we will investigate the role of LD diversification in protecting cancer cells from excess lipid peroxidation and ferroptosis. Moreover, we will determine whether modulation of LD diversification affects cancer development using a mouse model of liver cancer. Finally, the project will investigate how mechanisms controlling LD dynamics and subcellular localisation affect cellular bioenergetics and stress response in cancer cells. The results anticipated from this project will provide comprehensive insight into the role of LD heterogeneity in liver cancer.
DFG Programme
Research Units
