Project description
Understanding and targeting formate metabolism in cancer metastasis
In most cases, cancer metastasis is not curable, making it imperative to understand the complex mechanisms of metastases. Metastasising cancer cells exhibit metabolic plasticity enabling them to adapt to new environments. For example, cancer cells use the folate-mediated one-carbon (1C) cycle for serine catabolism rather than the formate-mediated pathway, allowing formate excretion from cancer cells. Furthermore, mitochondrial metabolism and increased extracellular formate concentrations promote cancer metastasis. However, the mechanisms and intermediates are not known. The ERC-funded 4M8 project aims to address these questions using genetic approaches and newly developed analytical methods, while also developing a tool to target formate directly in cancer cells.
Objective
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. 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 characterised by formate excretion from cancer cells. 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. 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 and (3) exploit formate overflow for cancer cell killing by directly targeting the formate molecule. 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 analyse the metabolic state in human tumour samples. Finally, we will develop a novel tool to target formate directly within cancer cells. 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.
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
This project's classification has been validated by the project's team.
Keywords
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2023-COG
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1445 Strassen
Luxembourg
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