Restoring balance in the bone marrow in tumor metastases

Neuroblastoma, a rare but aggressive pediatric cancer, often metastasizes to the bone marrow, making treatment difficult. With a LSBR fellowship for 5 years, Ilse Timmerman will investigate how tumor cells manipulate the bone marrow microenvironment to modify outgrowth of stem cells to immune cells.

Hematopoietic stem cells in the bone marrow give rise to various blood cell types. In neuroblastoma patients, tumor cells in the bone marrow disrupt this process, leading to disrupted blood cell production and the need for frequent transfusions. Additionally, the immune system’s ability to combat the tumor cells is compromised, and the effectiveness of immunotherapy is reduced.

Ilse will focus on the complex interactions between tumor cells, mesenchymal stromal cells and hematopoietic stem cells and how that may lead to immune suppression. Uncovering these tumor-supportive mechanisms is expected to eventually pave the way to identify novel therapeutic targets to restore the bone marrow and thereby counteract immunosuppression.

The approach

This research will be conducted in three phases:

1. Bone marrow samples will be obtained from neuroblastoma patients with and without bone marrow metastases, and compared to healthy bone marrow samples.
2. Tumor cells will be introduced into a 3-D bone marrow model ("bone marrow-on-a-chip"), previously developed at Sanquin. This will allow for the investigation of the changes induced by the tumor cells within the microenvironment.
3. Based on the findings from the in vitro model, possible key factors involved in tumor-induced bone marrow disruption will be identified. These factors will be individually manipulated in the model to assess their impact and potential as therapeutic targets.

The BM-on-a-chip culture model. 3D confocal microscopy images showing hematopoietic stem and progenitor cells (blue), endothelial cells (marked by its junctions in red), mesenchymal stromal cells (magenta) and neuroblastoma tumoroids (yellow) cultured in our BM-on-a-chip model

Ilse: "We hope to discover novel therapeutic avenues to effectively improve immunotherapy, benefiting children with neuroblastoma as well as patients with other bone marrow-metastasizing tumors.”

The research will be conducted together with Carlijn Voermans (Sanquin) and Lieve Tytgat and Mirjam Belderbos (Prinses Máxima Center).