Overview

My research program aims to better understand how the immune system can be used to treat childhood diseases. In children with cancer, the immune system is no longer able to rid the body of cancerous cells. In children with autoimmune diseases the immune system gets rid of healthy cells of the body. We are particularly interested in the metabolism of immune cells. Metabolism consists of all the chemical processes that occur within a living organism that maintain life. In immune cells this means that building blocks (metabolites) need to be brought in to allow the duplication of a cell by making all crucial parts of new cells. In fast growing immune cells this is especially demanding, since they need to duplicate themselves very rapidly to protect against attacks on the normal function of our bodies by, for instance, infections or cancer. This requires a variety of building blocks, and a lot of energy. For this process, cells can acquire these building blocks from their environment, or make them via intricate biochemical pathways. When the right building blocks are not available, immune cells fail to increase in numbers and cannot perform their job.

We use biochemical and metabolomic techniques to understand what fuel is needed for immune cell function, and how immune cells sense the fuel that is available in their environment.

By closely collaborating with Clinicians and Clinician scientists at BCCHR we are aiming to apply the findings to design better treatments for children with immune related diseases.

Publications

A metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways
Nature Communications
DOI: 10.1038/s41467-018-05311-4
2018

Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2
Immunity
DOI: 10.1016/j.immuni.2018.10.011
2018

Establishment of a transgenic mouse to model ETV7 expressing human tumors
Transgenic Research
DOI: 10.1007/s11248-018-0104-z
2018

Unraveling the Complex Interplay between T Cell Metabolism and Function
Annual Review of Immunology
DOI: 10.1146/annurev-immunol-042617-053019
2018

ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer
Science Advances
DOI: 10.1126/sciadv.aar3938
2018

Caught in the cROSsfire: GSH Controls T Cell Metabolic Reprogramming
Immunity
DOI: 10.1016/j.immuni.2017.03.022
2017

Mitochondrial Priming by CD28
Cell
DOI: 10.1016/j.cell.2017.08.018
2017

Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming
Cell
DOI: 10.1016/j.cell.2016.05.035
2016

High MN1 expression increases the in vitro clonogenic activity of primary mouse B-cells
Leukemia Research
DOI: 10.1016/j.leukres.2015.05.013
2015

Zebrafish etv7 regulates red blood cell development through the cholesterol synthesis pathway
DMM Disease Models and Mechanisms
DOI: 10.1242/dmm.015123
2014

PAX3-FOXO1 induces up-regulation of Noxa sensitizing alveolar rhabdomyosarcoma cells to apoptosis
Neoplasia (United States)
DOI: 10.1593/neo.121888
2013

MN1 overexpression is an important step in the development of inv(16) AML
Leukemia
DOI: 10.1038/sj.leu.2404778
2007

Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes
Blood
DOI: 10.1182/blood-2004-09-3742
2005

Research

The role of metabolism in regulation of function in immune cells
My lab aims to better understand the role of metabolism in regulation of function in immune cells. We aim to expand our understanding of the role of metabolism in the dysfunction of immune cells in cancer, and their hyperactivation in autoimmune conditions.

When cells are confronted with changing environments they have to adapt to their new surroundings to maintain cellular function. This adaptation is especially relevant for immune cells that move throughout the body and encounter different levels of metabolites and nutrients in the blood, tissues or tumours they traverse. The availability of nutrients influences immune cell metabolism, but having a metabolite available does not mean a cell will necessarily use it.

Cellular metabolism consists of an interconnected network that is influenced by at least 4 factors which we aim to better understand:

1. Metabolite availability
How do immune cells sense their nutritional environment, and how are these signals transmitted?

2. Metabolite transport into the cell
How are metabolite transporters regulated during immune cell activation?

3. Metabolic enzyme expression
Metabolic enzymes are often considered "household genes" for control experiments. How is activity of these enzymes modulated?

4. Availability of enzyme cofactors
Most, if not all, metabolic enzymes are dependent on substrate and cofactors. We are interested in the sensing of cofactor status and their effects on metabolic pathway flux.

Not all immune cells use the same metabolic pathways even if metabolites are abundant, transporters and enzymes are expressed, and cofactors are available. The response can be regulated by growth factors, cytokines, or immune cell receptor signaling, and we aim to better understand the signals that provide the instructions for which metabolic pathway to use.