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Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal
Nor Eddine Sounni1, Jonathan Cimino2, Silvia Blacher1
1Laboratory of Tumor and Developmental Biology, GIGA-CANCER, University of Liege, 4000 Liege, Belgium.
Abstract:
The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets.
Insights
Tumors adapt to antiangiogenic therapies by shifting metabolism towards carbohydrates and lipids, promoting regrowth and metastasis. Inhibiting lipid synthesis may counter this adaptation, offering new therapeutic strategies.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Antiangiogenic therapies targeting vascular endothelial growth factor (VEGF) are crucial cancer treatments.
- Mechanisms of tumor resistance and adaptation to antiangiogenic therapies remain incompletely understood.
- Tumor adaptation involves complex molecular and metabolic reprogramming.
Purpose of the Study:
- To elucidate the molecular mechanisms behind tumor adaptation to antiangiogenic therapy.
- To investigate the metabolic shifts occurring in tumors during and after antiangiogenic treatment.
- To identify potential therapeutic targets for overcoming resistance to antiangiogenic therapies.
Main Methods:
- Transcriptomic, proteomic, and metabolomic analyses were performed on preclinical cancer models.
- Tumor responses to sunitinib and sorafenib treatment and withdrawal were evaluated.
- Pharmacological inhibition of lipogenesis (orlistat) and gene silencing (shRNA) were employed.
Main Results:
- Antiangiogenic treatment led to tumor hypoxia and increased glycolysis.
- Treatment withdrawal resulted in tumor regrowth, restored angiogenesis, and enhanced lipid synthesis.
- Metabolic shift towards lipid metabolism correlated with increased metastatic dissemination.
- Inhibition of lipogenesis or fatty acid synthase suppressed tumor regrowth and metastasis after treatment withdrawal.
Conclusions:
- Tumors adapt to antiangiogenic therapy through a metabolic shift favoring carbohydrate and lipid metabolism.
- This metabolic adaptation promotes tumor regrowth and metastasis upon treatment cessation.
- Targeting lipid metabolism pathways presents a promising strategy to overcome resistance to antiangiogenic treatments.
