Metabolomics of programmed cell death
EMSL Project ID
50419
Abstract
Lipidomics is the study of cellular lipids to understand the function and structure of biological systems. The interaction of lipids with other cellular components, including proteins and metabolites, enables a greater understanding of the mechnisms behind lipid metabolism and homostasis. Lipids may act as therapeutic targets for aberrant lipid metabolism, as symptoms of disease, and serve as disease biomarkers. Targeted therapeutics directed at specific biological processes are emerging as the treatment of choice, for both human and animal diseases. Extrapolating the concept of targeted intervention to other systems, such as plant systems involved in biomass production for biofuels, is one potential application of synthetic biology to enhance our ability to manipulate biological systems for human benefit. The relationship between metabolic processes and regulated cell death has been extensively studied. However, in cancer despite initial clinical responses to inhibition of VEGFR, mTOR and the immune checkpoints, complete and durable responses to these agents are rare, and eventual resistance to each agent is nearly universal. The molecular vicissitudes exploited by tumors to escape treatments include hijacking bypass pathways, kinase receptor amplifications, second site mutations and microenvironmental factors, the latter in the context of immune checkpoint inhibitors. Clinically, inhibition of the PI3K-AKT-mTOR pathway in cancer cells imposes a dormant, nutrient-deprived state but not necessarily death, and consequently this has achieved limited therapeutic success. This treatment induced adaptive change can promote an incomplete response and the emergence of drug resistance in the surviving persister cells. In this proposal we will explore the metabolic changes to inhibition of the PI3K-AKT-mTOR pathway, specifically aborations in lipid metabolism. Two human kidney cancer cells, will undergo treatments that results in potent inhibition of the PI3K-AKT-mTOR pathway and induction of ferroptosis. Lipids, metabolites, and proteins will be extracted from the samples and analyzed using mass spectrometry All samples will undergo untargeted analysis with the exception of oxylipids, which will be conducted in a targeted fashion.
Project Details
Start Date
2018-07-09
End Date
2020-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members