RESEARCH

**Metabolic Interaction in the Stem cell Niche in the Intestine.** *Rodríguez-Colman, et al. **Nature** **543,** 424–427 (2017).*

Metabolism and Stem Cells

The intestinal epithelium entirely self-renews every 4-7 days. Intestinal stem cells actively divide and differentiate giving rise to all cell types in the intestine. In several tissues, metabolic changes occur along and even drive stem cell differentiation. Our research shows that in the intestine the different cell types display distinct metabolic phenotypes. As a matter of fact, we showed that mitochondrial activity is key in the maintenance of stem cell function.
Currently, we apply organoid technology to investigate the cross-talk between cellular metabolism and cell signaling and how this orchestrates stem cell differentiation in normal and tumourigenic tissue.

**Mitochondria in tumour organoids derived from colorectal cancer patients.** DNA staining shows aberrant chromosome organization (in cyan). Staining of mitochondria (in orange) indicates metabolic heterogeneity .

Tumour Heterogeneity

Within a tumour, cancer cells sharing the same genetic mutations can display phenotypic differences that result in, e.g., differential response to chemotherapy. Derailed metabolism is a Hallmark of Cancer and the Warburg effect is one of the most conserved phenotypes defining tumour metabolism. Our live imaging-based single cell analysis indicates that tumour heterogeneity also occurs at the level of metabolism. We investigate the metabolism of cancer cells and how to exploit metabolic dependencies to enhance the efficacy of conventional chemotherapy.

Metabolism and Cell Cycle

The cell cycle is tightly regulated. Specific events take place in each cell cycle phase and cellular metabolism adjusts to support them. The occurrence of metabolic oscillations and their cross-talk with the cell cycle has been investigated in unicellular yeast.
In our group we investigate the occurrence of metabolic fluctuations along the cell cycle and how these two events interact with each other. We study these processes both in cell lines cultures and in organotypic cultures.

**Tracking Metabolism with high temporal and spatial resolution.** In our group we are interested in metabolic changes as driving forces of cell fate. We combine the FUCCI system and FRET sensors to follow metabolic oscillations during the cell cycle.

The Importance of Nutrition in Cancer

“Let food be thy medicine, and let medicine be thy food”

Diet has an important role in the development of colorectal cancer (CRC). In fact, the links between diet, weight, and CRC risk are of the strongest for any type of cancer. However, the molecular mechanisms as how diet affects CRC remain ill defined, limiting the development of dietary-based (adjuvant) therapeutic strategies. In our group, we investigate the impact of specific dietary conditions on intestinal health, tumor growth and chemotherapy response. Importantly, our reductionist approach makes use of human derived organoids to define the molecular mechanisms behind the metabolic effects on intestinal health.

Health Holland-TKI funded. Co-applicant: Professor Dr. Saskia van Mil (UMC Utrecht). In collaboration with DSM, an international company with longstanding expertise in animal and human nutrition. With insights of the Cancer Epidemiology Julius Center (UMC Utrecht).