The role of Palmitoylation ERASERs in cancer metastasis

Introduction

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.

Discovery of Palmitoylation

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.

Hypothesis

Therefore, I hypothesize that, in palmitate-rich conditions (e.g., under a high-fat diet), palmitoylation anchors 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.

Research Objectives

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.
3. Assess how organ microenvironments and palmitate-rich diet conditions affect eraser activity.

Methodology

I will address this by integrating multi-omics, molecular biology, and mass spectrometry techniques with clinically relevant in vivo metastasis models.

Conclusion

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 the clinical translation of these findings by defining which patients will respond most effectively to palmitoylation-based therapies.