Cancer Metabolism

Understanding tumour development by unravelling metabolic rewiring in cancer cells

Changes in cellular metabolism are widely recognised as a hallmark of cancer cells. Tumour initiation, growth and proliferation depend heavily on the metabolic rewiring of cancer cells. Moreover, metabolites and metabolic enzymes influence gene and protein expression and impact surrounding non-cancerous cells through extracellular signalling, thereby creating an environment that supports tumour development and progression. Cancer cells can become reliant on their metabolic reprogramming, making cancer metabolism a vulnerability that can be exploited for therapy.

Our group studies these metabolic alterations in cancer cells, focusing on liver cancer, with the aim to identify novel metabolic targets for therapy. To achieve this, we develop and apply advanced model systems and metabolomic, lipidomics and isotope tracing analyses, combined with biochemical and cell biological approaches. In collaboration with others, we apply our knowledge on cancer metabolism to other types of cancer, too.

Metabolic rewiring is a vulnerability of cancer cells. We want to exploit that for therapy

Metabolomics

Metabolic rewiring also affects how cancer cells respond to treatment. It plays a key role in drug sensitivity and resistance. We use mass spectrometry-based metabolomics approaches to detect metabolic changes in drug-resistant cancer. This helps us understand how drugs work and how cells adapt their metabolism in response to treatment. 

Our focus is on proteasome inhibitors. These drugs show strong potential against hematologic tumors, but resistance and adverse effects limit their use. By studying how cancer cells adapt to these inhibitors, we aim to find new drug targets. This knowledge could guide combination therapies and improve outcomes for resistant patients.

The Utrecht Metabolism Expertise Center (MEC)

Our lab houses The Utrecht Metabolism Expertise Center (MEC), a facility specialized in cellular metabolomics and lipidomics. Using state-of-the-art mass spectrometry, we identify and quantify small molecules (metabolites and lipids) in biological systems with high precision. 

MEC offers a full range of approaches, including targeted and untargeted metabolomics, lipidomics and fluxomics with stable-isotope tracers to track dynamic pathway activity. Our expertise covers areas such as cancer metabolism and immune metabolism, and we have experience work with a wide variety of model systems and sample types.  

We provide full metabolomics and lipidomics support, from experimental design to data interpretation and visualization, helping researchers to translate metabolic measurements into biological understanding.

It is our mission to translate metabolite and lipid measurements into meaningful insights into the biological system at hand

Hepatic stellate cells

Hepatic stellate cells (HSCs), also known as Ito cells or lipocytes, make up 5–15 percent of liver cells. Under physiological conditions, HSCs are present in their quiescent state, storing fat and vitamine A. In liver fibrosis, HSCs are activated and transform into myofibroblasts that produce retinoids, inflammatory mediators, and extracellular matrix (ECM) components.

HSC activation is also central to cancer progression, as activated HSCs serve as a major source of cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC) and metastasis. 

Understanding the molecular mechanisms driving HSC activation offers insight into pathogenic mechanisms and opportunities for targeted therapies. Using primary cells under various co-culture conditions with other liver cells and cancer cells, we study quiescent, activated, and other HSC phenotypes to uncover key pathways that regulate the cellular heterogeneity.

A molecular basis for understanding diseases is crucial to develop novel drugs

MASH-in-a-dish

By the 2040s, one-third of the global population may have metabolic dysfunction-associated steatotic liver disease (MASLD). 0.3–2.2 percent of the patients will progress annually to metabolic dysfunction-associated steatohepatitis (MASH), a severe form that can lead to liver fibrosis, cirrhosis, or liver cancer. Dietary intervention and lifestyle modification remains the mainstay treatment for MASH patients. 

MASH begins when lipid-damaged hepatocytes interact with immune cells (e.g. Kupffer cells) and stromal cells (e.g. hepatic stellate cells), exchanging metabolites that promote inflammation and fibrosis. Studying this is challenging because isolating cells disrupts metabolism. To address this, we developed a MASH-in-a-dish system using liver organoids with Kupffer and hepatic stellate cells, enabling rapid cell separation and metabolite analysis to study disease mechanisms and potential therapies.

Uniquely, MASH-in-a-dish enables rapid separation of different liver cells for profiling metabolomics and understanding metabolite crosstalk in fatty liver diseases