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The role of Palmitoylation ERASERs in cancer metastasis

Project description

Researchers target lethal cancer spread

Metastasis, the silent assassin in cancer, claims countless lives annually. Unfortunately, it has long eluded effective treatment. Recent breakthroughs reveal palmitate, a fatty acid, as a key player in fuelling metastasis. In this context, the ERC-funded PalmERASERs project will help decode the mystery behind palmitate’s unique pro-metastatic impact. The discovery of palmitoylation, a modification crucial for metastasising breast cancer cells, has sparked intrigue. Researchers hypothesise that palmitoylation ‘erasers’ are pivotal in sustaining pro-metastatic effects. The project aims to define erasers’ influence on pro-metastatic signalling, explore their regulation and assess their activity under diverse conditions. PalmERASERs holds promise as a proof of concept for palmitoylation-based therapies, potentially revolutionising metastasis prevention and treatment.

Objective

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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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2023-STG

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Host institution

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 495 519,00
Address
CALLE SERRANO 117
28006 MADRID
Spain

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Region
Comunidad de Madrid Comunidad de Madrid Madrid
Activity type
Research Organisations
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 1 495 519,00

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