Many tumors are known to exhibit pathological alterations within the SMARCA4 gene. In the field of pediatric neuro-oncology, this is especially true for rhabdoid tumors and medulloblastomas. For rhabdoid tumors, the Schüller research group has shown that tumors with SMARCA4 mutations represent a distinct subgroup that can be well differentiated clinically and molecularly from other rhabdoid tumors (see Holdhof et al. Acta Neuropathol 2021). Within medulloblastomas, such mutations have been most frequently reported in WNT medulloblastomas and group 3 medulloblastomas. However, the function of these alterations is often unknown. Thus, in a variety of ways, the researchers are elucidating what role SMARCA4 plays in the development of the nervous system (see e.g. Holdhof et al., Development 2021) and in the pathogenesis of tumors of the nervous system. In doing so, they aim to find out when, where, and how a functionally intact SMARCA4 is required for brain development, how a pathologically altered SMARCA4 can initiate or accelerate tumor development, whether it contributes to metastasis and/or is associated with more aggressive tumor growth, and to what extent SMARCA4 can play a role as a potential target for anticancer therapy.

Atypical teratoid/rhabdoid tumors (AT/RT) are rare, highly aggressive tumors that occur in the spinal cord and brain. The exact cellular origin of these tumors is still not entirely clear, even though the Schüller group has already made relevant contributions to this topic (see e.g. Moreno et al. J Neurosci 2014; Graf et al. Nat Commun, 2022). Rhabdoid tumors usually occur in the first twelve months of a child's life. They are caused by mutations in two different genes, SMARCA4 and SMARCB1. The prognosis for these young patients is particularly poor if the tumor recurs or even metastasizes. At this point, very few treatment options are available because the mechanisms leading to recurrence or metastasis are largely unknown. Therefore, the research group is conducting intensive research to understand which characteristics distinguish recurrent tumors from primary tumors.

The scientists are working at the genetic, epigenetic and transcriptional level to functionally validate mutations specific to recurrent tumors and to test – both in vitro and potentially also in vivo – how such changes are suitable as anticancer drug targets.

Ependymomas are tumors of the central nervous system, some of which grow very aggressively. They arise from degenerated cells of the brain or spinal cord. While intracranial tumors occur mainly in childhood, spinal ependymomas are seen mainly in adulthood, unless neurofibromatosis is present, which can be associated with such spinal tumors at an early age (see, e.g., Kresbach et al., Acta Neuropathol 2021; Kresbach et al., Brain Pathol 2022). The research group is currently working intensively on the correlation of morphological and molecular characteristics with the clinical course of these diseases. In doing so, the researchers are also focusing on the inter- and intratumoral heterogeneity of the tumors, the clinical significance of which has received little attention to date. The methods used include global methylome analyses and DNA and RNA sequencing, which may even be performed at the single cell level or spatially resolved (scSeq or spatial omics analysis).