A new role for formate: how cancer reprograms lung cells to drive metastasis

LIH researchers contribute to important study on cancer metabolism

• Cancer Metabolism Group
• Cancer
• Department of Cancer Research

A new publication in the leading journal Cancer Discovery elucidates a novel mechanism through which metastatic cancer cells exploit healthy lung cells to fuel their metastatic growth in the lungs. The study, led by the VIB-KU Leuven Center for Cancer Biology in collaboration with The Francis Crick Institute, provides clinical relevant context to previous findings from the Cancer Metabolism Group of the LIH Department of Cancer Research (DoCR). In their study they have uncovered that the small metabolite formate contributes to metastasis formation. This study now points to new therapeutic strategies that target lung cells, rather than cancer cells themselves.

A critical aspect of metastasis formation is the establishment of a specialised microenvironment in distant organs that supports the proliferation of cancer cells. Within this environment, healthy cells are hijacked and forced to provide cancer cells with essential signals for their survival and growth, further promoting tumour progression. In breast cancer-derived lung metastasis, a specific type of lung cell known as alveolar type II (AT2) has been shown to prepare distant organs for the arrival of cancer cells.

In this context, the study led by Prof Sarah-Maria Fendt of the VIB-KU Leuven Center for Cancer Biology investigated how AT2 cells interact with breast cancer-derived lung metastases to better understand their role in tumour growth. The team discovered that cancer cells recruit AT2 cells and reprogram them to produce more lipids necessary to their survival. The researchers also found that reducing the amount of available lipids derived from AT2 cells hindered the cancer from growing further, thereby opening up new potential therapeutic avenues.

A key contribution from Dr Johannes Meiser and his team was the identification of formate as one of the critical signals responsible for this metabolic rewiring. Indeed, in a previous study published in Cell Reports, Dr Meiser showed that formate can alter lipid metabolism in cancer cells through SREBP activation, affecting the production of lipids such as LPC and LPE. The new study now extends this concept to the tumour microenvironment, where cancer-derived formate influences more than just tumour cells themselves, acting instead as a signal that attracts local healthy AT2 cells and alters their lipid homeostasis, thereby promoting metastatic outgrowth.

This finding provides direct evidence that formate plays a role in the physiology of breast cancer derived lung metastasis,

says Dr Meiser.

Overall, the study provides compelling evidence that metastases depend on metabolically reprogrammed host cells and identifies lipid metabolism in AT2 cells as a potential therapeutic target. It also reinforces the emerging concept, that formate is a central metabolic driver of cancer progression. This achievement underscores the strength of international collaboration and highlights LIH’s continued commitment in advancing cutting-edge cancer research.

Link to the original press release:

Blocking lipid production in healthy lung cells can reduce lung metastasis