Laboratory of Cellular Metabolism and Metabolic Regulation

We are tackling cancer and in particular metastasis formation as a metabolic disease. The rationale for this innovative approach is based on the fact that cancer and specifically metastasizing cells have to dynamically alter their cellular phenotype during disease progression, which in turn requires metabolic changes. Therefore, the overarching vision of my laboratory is to mechanistically dissect the metabolic vulnerabilities of (metastasizing) cancer cells in the context of the tumor microenvironment and the metastatic niche to define novel therapeutic approaches to prevent cancer progression.

Q&A: Metastasis Metabolism

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Do cancer cells have placticity in their lipid metabolism?

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Most tumours have an aberrantly activated lipid metabolism that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation. This suggests that many cancer cells contain an unexplored plasticity in their fatty acid metabolism. Here we discovered that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, mouse hepatocellular carcinomas, and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that synthesize sapienate impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers... Vriens & Christen et al, 2019, NatureTriki et al, 2020, Cell Reports

Metabolic hallmarks of metastasis formation

Metastasis to distant organs is a predictor of poor prognosis. Therefore, it is of paramount importance to understand the mechanisms that impinge on the different steps of the metastatic cascade. Recent work has revealed that particular metabolic pathways are rewired in cancer cells to support their transition through the metastatic cascade, resulting in the formation of sec- ondary tumors in distant organs. Indeed, metabolic rewiring induces signaling pathways during initial cancer invasion, circulating cancer cells depend on enhanced antioxidant defenses, and cancer cells colonizing a distant organ require increased ATP production. Moreover, the local environment of the metastatic niche dictates the metabolic pathways secondary tumors rely on. Here we describe mechanisms of metabolic rewiring associated with distinct steps of metastasis formation... Elia et al., 2018 Trends in Cell Biology

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Can we inhibit metastasis formation by targeting cancer metabolism?

diagrame 3The extracellular matrix is a major component of the local environment—that is, the niche—that determines cell behavior. During metastatic growth, cancer cells shape the extracellular matrix of the metastatic niche by hydroxylating collagen to promote their own metastatic growth. However, only particular nutrients might support the ability of cancer cells to hydroxylate collagen, because nutrients dictate which enzymatic reactions are active in cancer cells. Here we discovered that breast cancer cells rely on the nutrient pyruvate to drive collagen-based remodeling of the extracellular matrix in the lung metastatic niche. Specifically, we discovered that pyruvate uptake induces the production of alpha-ketoglutarate. This metabolite in turn activates collagen hydroxylation by increasing the activity of the enzyme collagen prolyl-4-hydroxylase. Inhibition of pyruvate metabolism was sufficient to impair collagen hydroxylation and consequently the growth of breast-cancer-derived lung metastases in different mouse models. In summary, we provide a mechanistic understanding of the link between collagen remodeling and the nutrient environment in the metastatic niche... Elia et al, 2019, Nature

Can we inhibit metastasis formation by targeting cancer metabolism?

diagrame 4We are investigating how the metabolism of cancer cells changes during metastasis formation. We discovered that proline catabolism via proline dehydrogenase (Prodh) supports growth of breast cancer cells in 3D culture by providing energy in form of ATP. Subsequently, we linked proline catabolism to in vivo metastasis formation. In particular, we found that PRODH expression and proline catabolism is increased in metastases compared to primary breast cancers of patients and mice. Moreover, inhibiting Prodh was sufficient to impair formation of lung metastases in the orthotopic breast cancer mouse models, without adverse effects on healthy tissue and organ function. In conclusion, we discovered that Prodh is a potential drug target for inhibiting metastasis formation…Elia et al, 2017, Nature Communications

Does the microenvironment shape the metabolism of cancer cells during metastasis formation?

diagrame 5We investigated the role of the microenvironment in shaping cancer metabolism during breast cancer metastasis to the lungs. We discovered that breast cancer-derived lung metastases activate PC-dependent anaplerosis as a function of the nutrient availability within the lung microenvironment. While primary breast cancers often rely on glutamine anaplerosis, the resulting and genetically similar lung metastases activate PC-dependent anaplerosis in response to the lung microenvironment. Thus, we discovered that pyruvate carboxylase-dependent anaplerosis distinguishes lung metastases from their corresponding primary breast cancers. This shows that primary cancer and their resulting metastases can have different metabolic vulnerabilities and consequently should be targeted with different drugs. … Christen et al., 2016, Cell Reports


 

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