Current Research and Scholarly Interests
The Petritsch lab broadly investigates underlying causes for the intra-tumoral heterogeneity and immune suppression in brain tumors from a developmental neuro-developmental perspective. Proper cell fate decisions by neuroglia stem cells are critical for growing the cell lineages that form the brain during development and to maintain adult brain homeostasis. The mechanisms for cell fate decisions in the human brain are largely unknown. By using patient-derived cells from brain surgeries, we investigate cell fate decision mechanisms in the normal brain and in brain malignancies. We think that defective cell fate decisions fuel the intra-humoral heterogeneity and plasticity that makes treatment of human brain tumors so challenging. We therefore work to gain an understanding of how brain cells control the fate of their progeny, whereby we unravel novel points of vulnerabilities in brain tumor cells, that could be exploited therapeutically.
Excessive proliferation, apoptotic evasion, and migratory spread are all hallmarks of tumorigenesis. However, these defects fail to explain the incredible heterogeneity and immune suppression observed in malignant brain tumors, two major hurdles to their treatment, which remains mostly palliative.
In the healthy brain, neuroglia stem cells generate progenitors, which in turn give rise to differentiating cells that will eventually acquire their final functional state. Cell fate decisions within these hierarchical brain cell lineages are tightly controlled and irreversible: e.g. cells in the state of differentiation will not turn into progenitor cells or stem cells. It is known that brain tumor cells, on the other hand, defy many general principles of neurobiology. This is especially true for malignant glioma cells, which simultaneously express markers of different lineages and states exhibiting incomplete differentiation. Tumor cell hierarchies are poorly understood, providing no explanation for why tumor cells with stem-like, progenitor-like, and differentiated features co-exist and interact with normal brain cells and immune-infiltrating cells within a single tumor entity, and how this heterogeneity relates to the lack of active immune infiltration.
Defects in cell fate control could explain many key defects present in brain tumors Of special emphasis, we study the establishment of cell fates within normal hierarchical brain lineages for comparison to the dysregulated cell-fate hierarchies seen in brain tumors. Our lab was the first to demonstrate that normal adult oligodendrocyte progenitor cells (OPCs) undergo asymmetric divisions to make cell fate decisions, i.e. to generate OPCs as well as differentiating cells each time they divide. Drawing from these data, we investigate whether brain tumors divide along hierarchical lineages and how oncogenic mutations might affect cell fate decisions within these hierarchies. A major line of investigation in our lab focuses on whether defects in asymmetric division lead to aberrant cell fate decisions that cause the paradigm mixed lineage phenotypes and the intra-tumoral heterogeneity present across tumors. We complement our work with human cells with orthotopic and genetically engineered mouse models of gliomagenesis to conduct molecular, cellular and bioinformatic analyses