Summary
Metastasis is the major cause of death in patients with cancer. A better understanding of the mechanisms driving metastasis is critical to develop more effective anti-cancer treatments. The fatty acid palmitate has been recently identified as fuel for metastasis-promoting pathways. However, why palmitate has such a unique pro-metastatic effect compared to other fatty acids with similar metabolic fates remains elusive. Strikingly, I discovered that palmitoylation, a reversible post-translational protein modification driven solely by palmitate, is essential for metastasizing breast-cancer cells. Unexpectedly, I found that palmitoylation ‘erasers’, enzymes that remove the modification, are essential to sustain pro-metastatic effects of palmitate during metastatic colonization. Therefore, I hypothesize that, in palmitate-rich conditions (e.g under high-fat diet), palmitoylation anchor oncogenic proteins to membranes to get activated (functioning as a priming event), while erasers act as a rate-limiting release step, allowing primed proteins to engage in pro-metastatic signaling. I will investigate how the dynamics of palmitoylation promote metastasis by focusing on the erasers, whose role in metastasis remains largely unexplored. Specifically, I will: 1) define how erasers influence pro-metastatic signaling events in metastasizing cells; 2) investigate how erasers activity is regulated in metastasizing cells; and 3) assess how organ microenvironments and palmitate-rich diet condition eraser activity. I will address this by integrating multi-omics, molecular biology and mass spectrometry techniques with clinically relevant in vivo metastasis models. PalmERASERs will serve as a proof of concept for palmitoylation-based therapies with the goal of preventing or treating metastases. By focusing on the influence of diet, I will also enhance clinical translation of these findings by defining which patients will respond most effectively to palmitoylation-based therapies.
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| Web resources: | https://cordis.europa.eu/project/id/101116912 |
| Start date: | 01-01-2024 |
| End date: | 31-12-2028 |
| Total budget - Public funding: | 1 495 519,00 Euro - 1 495 519,00 Euro |
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Original description
Metastasis is the major cause of death in patients with cancer. A better understanding of the mechanisms driving metastasis is critical to develop more effective anti-cancer treatments. The fatty acid palmitate has been recently identified as fuel for metastasis-promoting pathways. However, why palmitate has such a unique pro-metastatic effect compared to other fatty acids with similar metabolic fates remains elusive. Strikingly, I discovered that palmitoylation, a reversible post-translational protein modification driven solely by palmitate, is essential for metastasizing breast-cancer cells. Unexpectedly, I found that palmitoylation ‘erasers’, enzymes that remove the modification, are essential to sustain pro-metastatic effects of palmitate during metastatic colonization. Therefore, I hypothesize that, in palmitate-rich conditions (e.g under high-fat diet), palmitoylation anchor oncogenic proteins to membranes to get activated (functioning as a priming event), while erasers act as a rate-limiting release step, allowing primed proteins to engage in pro-metastatic signaling. I will investigate how the dynamics of palmitoylation promote metastasis by focusing on the erasers, whose role in metastasis remains largely unexplored. Specifically, I will: 1) define how erasers influence pro-metastatic signaling events in metastasizing cells; 2) investigate how erasers activity is regulated in metastasizing cells; and 3) assess how organ microenvironments and palmitate-rich diet condition eraser activity. I will address this by integrating multi-omics, molecular biology and mass spectrometry techniques with clinically relevant in vivo metastasis models. PalmERASERs will serve as a proof of concept for palmitoylation-based therapies with the goal of preventing or treating metastases. By focusing on the influence of diet, I will also enhance clinical translation of these findings by defining which patients will respond most effectively to palmitoylation-based therapies.Status
SIGNEDCall topic
ERC-2023-STGUpdate Date
12-03-2024
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