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Projects / Programmes source: ARIS

Targeting lipid droplets to reduce cancer cell resistance to stress

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Research activity

Code Science Field Subfield
3.04.00  Medical sciences  Oncology   
1.05.00  Natural sciences and mathematics  Biochemistry and molecular biology   

Code Science Field
B000  Biomedical sciences   

Code Science Field
3.02  Medical and Health Sciences  Clinical medicine 
1.06  Natural Sciences  Biological sciences 
Keywords
Cancer, lipid droplets, autophagy, lipophagy, stress response, lipolysis, triglycerides, fatty acids, tumour, metastasis, bioluminiscence
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (18)
no. Code Name and surname Research area Role Period No. of publications
1.  55138  PhD Mauro Danielli  Biochemistry and molecular biology  Researcher  2021  18 
2.  15873  PhD Mateja Erdani Kreft  Neurobiology  Researcher  2019 - 2022  409 
3.  50498  PhD Adrijan Ivanušec  Biochemistry and molecular biology  Researcher  2022  27 
4.  38200  PhD Eva Jarc Jovičić  Biochemistry and molecular biology  Researcher  2019 - 2020  67 
5.  06628  PhD Roman Jerala  Biochemistry and molecular biology  Researcher  2019 - 2022  1,190 
6.  07673  PhD Dušan Kordiš  Biochemistry and molecular biology  Researcher  2019 - 2022  215 
7.  00412  PhD Igor Križaj  Biochemistry and molecular biology  Researcher  2019 - 2022  726 
8.  52369  Ana Kump  Biochemistry and molecular biology  Researcher  2020 - 2021  40 
9.  18802  PhD Adrijana Leonardi  Biochemistry and molecular biology  Researcher  2019 - 2022  156 
10.  21426  PhD Mateja Manček Keber  Pharmacy  Researcher  2019 - 2022  159 
11.  38275  Anja Perčič    Technical associate  2019 - 2022  0 
12.  56248  Leja Perne  Biochemistry and molecular biology  Technical associate  2022  11 
13.  20213  PhD Toni Petan  Biochemistry and molecular biology  Head  2019 - 2022  177 
14.  04570  PhD Jože Pungerčar  Biochemistry and molecular biology  Researcher  2019 - 2022  320 
15.  15600  MSc Maja Šimaga    Technical associate  2020 - 2022  5 
16.  21553  PhD Jernej Šribar  Biochemistry and molecular biology  Researcher  2019 - 2022  108 
17.  33100  PhD Larisa Tratnjek  Neurobiology  Researcher  2019 - 2022  62 
18.  39124  PhD Taja Železnik Ramuta  Biochemistry and molecular biology  Junior researcher  2019 - 2020  103 
Organisations (3)
no. Code Research organisation City Registration number No. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  90,706 
2.  0104  National Institute of Chemistry  Ljubljana  5051592000  20,982 
3.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  48,236 
Abstract
Cancer cells possess a remarkable ability to adapt to the inhospitable tumour microenvironment by modifying their metabolism to match nutrient supply. This metabolic plasticity is crucial for tumour growth, metastasis and resistance to therapy. The survival of cancer cells during stress depends on the availability of extracellular lipids and on their capacity to synthesize, mobilise or recycle their own intracellular lipids. Cancer cells dynamically switch between these lipid sources, which has hampered recent efforts to limit tumour growth using inhibitors of fatty acid synthesis. There is a pressing need to identify the pathways of lipid acquisition and utilization that may be targeted to reduce the resistance of cancer cells to stress. Lipid droplets (LDs), cytosolic fat storage organelles present in most cells from yeast to human, are emerging as major regulators of lipid metabolism, trafficking and signalling. Their biogenesis is induced in cells exposed to nutrient and oxidative stress and they accumulate in different cancers. LDs act as switches that coordinate lipid uptake, storage and use for different purposes in the cell, such as energy production, protection against oxidative stress or membrane biogenesis during rapid cell growth. They also sequester excess fatty acids and regulate their subsequent gradual release by lipolysis. This buffering and delayed release of lipids is a crucial aspect of LD biology that is exploited by aggressive cancer cells for protection against stress. Targeting the mechanisms of LD turnover in cancer cells may therefore reduce their resilience and inhibit tumour growth.  LDs engage in a complex and as yet poorly defined relationship with autophagy, the major cellular recycling machinery and stress response pathway. First, autophagy may drive LD biogenesis by providing lipids recycled from other membranous organelles. Second, autophagy may participate in LD breakdown through a selective form of autophagy named lipophagy. Third, LDs may promote autophagy by supplying lipids for the formation of autophagosomes, maintaining membrane homeostasis or stimulating signalling pathways. The interplay between LDs and autophagy may thus hold the key to our understanding of lipid dynamics in stressed cancer cells.  The major objective of this project is to discover the principal ways in which LDs cooperate with autophagy in different cancer cells and to reduce their resistance to stress by targeting critical points in the LD/autophagy axis. By studying the roles of the major enzymes involved in LD turnover in the context of activated or inhibited autophagy, over a range of different nutrient stress conditions, we will determine the interplay between the two processes and their importance for cancer cell survival during stress. Mechanistically, we will pinpoint the ways in which the LD/autophagy axis contributes to the maintenance of energy and redox homeostasis and for the regulation of membrane phospholipid composition during stress. This will be the first study to provide a lipidomic insight into the connections between autophagy, the LD lipidome and membrane composition in stressed cancer cells. Finally, using a xenograft mouse model we will evaluate for the first time the feasibility of targeting the LD/autophagy axis for reducing tumour growth in vivo. We are confident that this project will open new perspectives in cancer research by targeting the central lipid metabolism and stress-associated organelle – the lipid droplet.
Significance for science
Originality, relevance and potential impact of the results    1. The importance of lipid metabolism in cancer is emerging. Lipid droplets may be the nexus between cancer metabolism and cellular stress resistance and this project will provide original results that will have an impact on both research fields.   2. Lipid droplets accumulate in cancer cells and enable their survival during stress. Finding the critical mechanisms used by cancer cells to exploit this organelle will boost basic and clinical research in the field and lead to new therapeutic and preventive strategies.   3. Targeting metabolic pathways that are the converging point and common strategy for the survival of different and genetically heterogeneous types of tumours, may prove to be a better way to treat cancer than targeting specific oncogene and tumour-suppressor activated pathways.   4. The idea that targeting lipid droplets and autophagy/lipophagy may be relevant to the fight against cancer has been poorly explored and this study will provide pioneering new knowledge in the field.   5. The importance of lipid droplets and lipophagy in human disease is only beginning to emerge. This project will provide new knowledge of general interest for human biology, in particular in the contexts of aging, neurodegeneration, metabolic syndrome and obesity.    6. The unique international consortium providing expertise in the fields of lipids, lipolysis, LD biology, pathophysiology, drug design, immunity and cancer, with a vast experience in cell and molecular biology, synthetic biology, proteomics, lipidomics and mouse models of disease, guarantees research excellence and publications in journals with high impact factors.
Significance for the country
Originality, relevance and potential impact of the results    1. The importance of lipid metabolism in cancer is emerging. Lipid droplets may be the nexus between cancer metabolism and cellular stress resistance and this project will provide original results that will have an impact on both research fields.   2. Lipid droplets accumulate in cancer cells and enable their survival during stress. Finding the critical mechanisms used by cancer cells to exploit this organelle will boost basic and clinical research in the field and lead to new therapeutic and preventive strategies.   3. Targeting metabolic pathways that are the converging point and common strategy for the survival of different and genetically heterogeneous types of tumours, may prove to be a better way to treat cancer than targeting specific oncogene and tumour-suppressor activated pathways.   4. The idea that targeting lipid droplets and autophagy/lipophagy may be relevant to the fight against cancer has been poorly explored and this study will provide pioneering new knowledge in the field.   5. The importance of lipid droplets and lipophagy in human disease is only beginning to emerge. This project will provide new knowledge of general interest for human biology, in particular in the contexts of aging, neurodegeneration, metabolic syndrome and obesity.    6. The unique international consortium providing expertise in the fields of lipids, lipolysis, LD biology, pathophysiology, drug design, immunity and cancer, with a vast experience in cell and molecular biology, synthetic biology, proteomics, lipidomics and mouse models of disease, guarantees research excellence and publications in journals with high impact factors.
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