Neuroblastoma is a type of pediatric cancer that originates in immature nerve cells (neuroblasts) during embryo development. These tumors predominantly emerge from the adrenal glands atop the kidneys, although they can also develop in nerve tissues across the spine, chest, abdomen, or pelvis. Although neuroblastoma is not usually associated with known cancer-linked genes, a hallmark of aggressive neuroblastoma tumors is DNA abnormalities such as the striking amplification of the MYCN gene.
Crucial Research Discoveries in Neuroblastoma
The AMC Oncogenomics research group, previously led by Rogier Versteeg, identified additional genes involved in the formation and growth of neuroblastomas. Notably, in aggressive neuroblastomas, Versteeg's team identified significant abnormalities in genes responsible for neuritogenesis, the process involved in the formation of nerve sprouts.
The AMC Oncogenomics research group. After Rogier Versteeg retired the group has been incorporated into the section Oncogenetics of the department of Human Genetics, AmsterdamUMC.
From Neuritogenesis Genes to Targeting of Different Tumor Cells
Follow-up research on the role of neuritogenesis genes has shed light on an underlying molecular signaling pathway called Rac/Rho signaling. Disruption of this pathway had diverse effects across various types of neuroblastoma cell cultures. These observations aligned with variations seen in the regulation of cell mobility and cell growth, suggesting that neuroblastoma has different cellular manifestations. The focus of the research group shifted to understanding the role of cell plasticity within neuroblastoma – the tumor cells' ability to "change shape" or morphologically adapt, particularly under the stress of intensive treatment.
Shape-shifting Neuroblastoma Cells
These research efforts led to the important discovery that most neuroblastomas contain at least two distinct cell types: undifferentiated mesenchymal cells (MES) and committed adrenergic cells (ADRN). These cell types seemed to be able to interconvert and resemble cells from different lineage differentiation stages. This crucial breakthrough in unveiling the chameleon nature of neuroblastoma cells also explained a significant challenge in neuroblastoma treatment: while ADRN cells may respond to traditional therapies, MES cells often show resilience, contributing to treatment resistance and relapse, a common hurdle in neuroblastoma management.
Crafting Novel Therapeutic Strategies
The current research initiative funded by Villa Joep will focus on uncovering the vulnerabilities of each tumor cell type by exploring the mechanisms that underlie the transition between ADRN and MES cell types. The Oncogenomics research group succeeded in targeting ADRN cells with ALK inhibitors, a therapeutic treatment now commonly used in the clinic. However, the resistance of MES cells to this treatment highlights the need to target both cell types simultaneously.
The envisioned strategy is to use CRISPR functional genomics screen to find weaknesses in both ADRN and MES cells, aiming for more comprehensive combination therapies. Promising results from initial combination therapy trials in mouse models (also supported by Villa Joep) hint at the potential of this strategy to significantly improve treatment efficacy.
Integrating Advanced Technologies
The Oncogenomics group combines cutting-edge technologies, such as single-cell sequence analysis, ChIP sequence analysis, cell-specific tracking systems, and CRISPR to uncover the intricacies of neuroblastoma cell behavior during tumor progression and treatment. A deeper understanding will yield novel strategies to disrupt the tumor's ability to adapt and resist, in addition to paving the way to developing tailored therapies that are responsive to the tumor's evolutionary dynamics. Insights from this research may also contribute to a broader understanding of therapy resistance and cell plasticity. To integrate the data and work towards clinically translating the results, the group will collaborate with Jan Koster (Bio-informatics) and Jan Molenaar (Prinses Maxima Center).
Project: Tailored Combination Therapies to Target the Multiple Faces of Neuroblastoma
The principal investigators of the new project are Rob Wolthuis (left), Ellen Westerhout (center), and Linda Valentijn (right). The research will take place in close collaboration with Jan Molenaar (Prinses Máxima Centrum) and Jan Koster (CCA Bio-informatics group, LEXOR, AmsterdamUMC).
Previous research by the AMC Oncogenomics research group revealed that neuroblastoma consists of multiple types of cancer cells (ADRN and MES cells). Even though ADRN and MES cells share the same genetic material, they can exhibit vastly different characteristics, behaviors, and responses to treatment. This flexibility is due to the cells’ ability to turn specific genes "on" or "off” – dynamic regulation of gene expression.
Untreated neuroblastomas consist mainly of ADRN cells, with relatively few MES cells. Recent research by Ellen Westerhout and others showed that MES cells are insensitive to certain treatments, which allows them to hide, only to catalyze tumor regrowth once treatment is stopped.
In a novel promising approach, the addition of a drug targeting MES cells to standard therapy against ADRN cells showed a reduction in tumor re-growth. Building on this foundation, the current team at the Department of Human Genetics, headed by Rob Wolthuis, will use CRISPR technology to delve deeper into the vulnerabilities of neuroblastoma cell types.
The goal is twofold: to discover new drugs that can be integrated with existing treatment regimens to target the resistant cancer cells, and to innovate ways to inhibit the adaptive capabilities of treatment-sensitive cells.
This research project aspires to realize new and better targeted treatments for recurrent neuroblastomas and increase survival for affected children.
For more information contact Dr. Rob Wolthuis, read more about Amsterdam UMC’s CRISPR Expertise Center, or visit the website of Villa Joep.
Researchers involved at Cancer Center Amsterdam
Ellen Westerhout
Linda Valentijn
Jan Koster
Rob Wolthuis
This text is based on a Dutch article composed for Villa Joep. Translation and adaptation by New Haven Biosciences Consulting.