Formate-dependent Regulation of Cancer Metastasis

Introduction

Mechanisms underlying cancer metastasis are poorly understood and context dependent. An essential feature of disseminating cancer cells is metabolic plasticity, which allows cellular adaptation to changing environmental conditions along the metastatic cascade.

Discovery of Formate Overflow

I discovered in 2016 the phenomenon of formate overflow, an alternative pathway for serine catabolism via folate-mediated one-carbon (1C) cycle. Instead of using formate for nucleotide synthesis (to support proliferation), formate overflow is characterized by formate excretion from cancer cells.

Impact on Cancer Metastasis

Furthermore, I have convincingly demonstrated that mitochondrial 1C metabolism and increased extracellular formate concentrations promote cancer metastasis in a growth-independent manner. However, it remains unknown which intermediates of 1C metabolism contribute to this phenotype, how formate controls metastasis, and how it can be targeted therapeutically.

Research Objectives

To cross the current edge of knowledge, I will:

1. Take advantage of genetic and newly developed analytical methods to dissect how the formate-dependent effects are propagated in cells.
2. Describe intrinsic mechanisms to explain how the formate signal is relayed to promote metastasis.
3. Exploit formate overflow for cancer cell killing by directly targeting the formate molecule.

Novel Concept and Tool Development

4M8 will explain a novel concept of how a mitochondrial metabolic signal drives cancer cells towards a pro-metastatic phenotype and how this knowledge can be translated into a signature to analyze the metabolic state in human tumor samples.

Finally, we will develop a novel tool to target formate directly within cancer cells.

Conclusion

In sum, our research will shed light on an unexplored field of cancer metabolism, providing the foundation to develop novel treatment approaches against metastatic cancer, the primary cause of cancer death.