Projects / Programmes
The interplay between lipolysis and lipophagy in the modulation of ferroptosis in cancer
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
lipid metabolism, lipid droplets, lipid peroxidation, polyunsaturated fatty acids, redox metabolism, ferroptosis, cancer
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
55138 |
PhD Mauro Danielli |
Biochemistry and molecular biology |
Head |
2021 - 2023 |
18 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0106 |
Jožef Stefan Institute |
Ljubljana |
5051606000 |
90,987 |
Abstract
Cancer cells are exposed to metabolic and oxidative stress in their microenvironment. Persistent oxidative stress often leads to the oxidation of polyunsaturated lipids, thereby disrupting membrane and organelle function. Cancer cells have powerful antioxidant mechanisms that continuously remove oxidized lipids from cell membranes, thereby inhibiting the propagation of lipid peroxidation. Failure to repair lipid peroxides leads to ferroptosis, a recently discovered form of programmed cell death, which is emerging as an attractive therapeutic target in cancer. Given that ferroptosis depends on the oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids, the metabolic and signaling pathways that regulate the incorporation, removal and distribution of PUFAs in cell membranes could determine ferroptotic sensitivity. As central regulators of cellular fatty acid trafficking and metabolism, lipid droplets are emerging as potential modulators of ferroptosis. Lipid droplets (LDs) are cytosolic fat storage organelles present in most eukaryotic cells. They accumulate in tumours and cells exposed to oxidative and metabolic stress. LDs sequester excess fatty acids and control their gradual release from triglycerides by lipolysis. Lipolysis is catalyzed by neutral lipases, such as adipose triglyceride lipase (ATGL), which is responsible for fatty acid transfer to mitochondria for energy production, but it also modulates oxidative stress by controlling the release of PUFAs. Additionally, LDs may be broken-down by a selective form of autophagy, i.e., “lipophagy”, which engulfs LDs and delivers them to lysosomes for degradation by acid lipases and other hydrolases. Thus, the two processes are conceptually different, but they display a considerable crosstalk, which has only begun to be uncovered in recent studies. In particular, it is not yet known when, how and why cells decide to use one, the other or perhaps both mechanisms of LD breakdown. We hypothesize that depending on the particular stress conditions cancer cells employ lipolysis and/or lipophagy to serve different purposes in the cell, one being the regulation of PUFA distribution and membrane lipid peroxidation. Here, we aim to investigate the relative importance of lipolysis vs. lipophagy in the regulation of ferroptosis sensitivity in cancer cells. The major objective of this project is to find out if LD breakdown via lipolysis or lipophagy modulates the sensitivity of cancer cells to ferroptosis. By targeting the major enzymes responsible for lipolysis and lipophagy in the context of stimulated or inhibited lipid peroxidation, we will study the links between LD metabolism and ferroptosis. Specifically, we will address the hypothesis that LD breakdown drives membrane remodeling, thereby altering the availability of PUFAs within cell membranes. Our molecular and cell biology studies will be complemented by lipidomic analyses to determine how LD breakdown affects the PUFA trafficking between the triglyceride and phospholipid pools. Finally, we will assess the capacity of LD breakdown to modulate ferroptosis and tumor growth in vivo. By connecting three major stress response pathways – lipolysis, lipophagy and the cellular redox defense – this project will provide innovative ways to target cancer cell resilience and may lead to new therapeutic opportunities.
