Metastatic growth of cancer cells requires extracellular matrix (ECM) production. The understanding was that transcription factors regulate ECM production and thus, metastatic growth by increasing the expression of collagen prolyl 4-hydroxylase (CP4H, also known as P4HA). In contrast, we discovered that metabolism regulates CP4H activity independently of the known transcription factors. Specifically, we found that loss of pyruvate metabolism inhibits CP4H activity and consequently ECM–dependent breast cancer cell growth. Based on this discovery, we proposed the novel concept that metabolism regulates metastatic growth by increasing ECM production.
In this project, we investigated the following questions:
1) What is the mechanism by which pyruvate regulates CP4H activity in breast cancer cells?
We discovered that breast cancer cells rely on the nutrient pyruvate to drive collagen-based remodelling of the extracellular matrix in the lung metastatic niche. Specifically, we discovered that pyruvate uptake induces the production of α-ketoglutarate. This metabolite in turn activates collagen hydroxylation by increasing the activity of the enzyme collagen prolyl-4-hydroxylase (CP4H), hereby increasing ECM production.
2) How can this novel metabolic regulation be exploited to inhibit breast cancer-derived lung metastases growth?
We found that inhibition of pyruvate metabolism was sufficient to impair collagen hydroxylation and consequently, the growth of breast-cancer-derived lung metastases in different mouse models.
3) How can this novel regulation be translated to different metastatic sites and cancers of different origin?
As metastasizing cancer cells must adapt their metabolism to the nutrient environment of distant organs, we performed a loss-of-function CRISPR screen against Solute Carrier (SLC) transporters in a breast cancer mouse model to define nutrient requirements for lung and liver metastases. We identified SLC transporters that form a liability to lung and/or liver metastases from breast cancer, liver and colorectal cancer. Moreover, we also discovered that lipids are primed in future organs of metastasis due to the presence of tumour secreted factors or diet and that this promotes liver and lung metastasis formation from breast cancer via the activation of signalling cascades by posttranslational modifications. Furthermore, we found metabolic heterogeneity within the primary tumour, and in this respect, we discovered a completely new function of PHGDH, a rate-limiting enzyme in the serine biosynthesis pathway, namely its role in the metastasis initiating capacity of cancer cells and concomitant cancer cell plasticity (breast cancer and melanoma).
With this project, we delivered a novel concept by which metabolism regulates metastatic growth. Moreover, we identified additional targets in nutrient metabolism that impair metastasis formation. In a long-term perspective, we expect that targeting metabolism will pave the way for an unexplored approach to treat cancer metastases.
