Current Research and Scholarly Interests
We study cell fate mechanisms to understand intra-tumoral heterogeneity and overcome therapy resistance and immune suppression in brain tumors.
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. Only once we elucidate the underlying biologic causes for heterogeneity and immune suppression, will we develop better treatment options for brain tumor patients and prevent malignant progression and tumor growth.
In the healthy brain, neural 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.
The Petritsch lab broadly investigates underlying causes for the intra-tumoral heterogeneity and immune suppression in brain tumors from a developmental neurobiology perspective. Defects in cell fate control could explain many key defects present in brain tumors and an understanding of how brain cells control the fate of their progeny may identify novel points of vulnerabilities to target with therapeutics. 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.
To study interactions of tumor cells and the immune system, we have developed and utilized transplantable mouse glioma models. We are tasked to facilitate and coordinate the distribution of fresh tissue from the neurosurgery operating room, and have access to fresh brain tissue from patient surgeries, from which we prepare cell culture models for brain tumors and normal progenitors. We complement our work with human cells with studies in genetically engineered mouse models of gliomagenesis to conduct molecular, cellular and bioinformatic analyses