The Petritsch Lab studies the mechanisms by which neural stem and progenitor cells turn into brain tumor cells and how these propagate the tumor. We critically evaluate the cancer stem cell hypothesis which is proposed to explain how brain tumor grow and evade therapies. Our long-term goal is to find critical points of disruption in brain tumor cells to which novel anti-glioma therapies can be targeted and thereby make an impact for patients with high-grade gliomas.
For our studies we isolate stem and progenitor-like cells from surgical brain tumor specimens from patients at the Department of Neurosurgery, and premalignant and malignant murine neural stem cells. We analyze these in cell culture assays. In addition, we study and develop stem and progenitor cell-based in vivo models for gliomas with the purpose to use them for preclinical testing of novel therapies. We apply bioinformatic and molecular approaches to identify novel tumor suppressors and oncogenes in brain tumorigenesis.
Asymmetry-defective oligodendrocyte progenitors are oligodendroglioma precursors.
Our recent findings showed that post-natal oligodendrocyte progenitors (OPC) self-renew and generate mature oligodendrocytes by undergoing asymmetric cell divisions. With our colleagues we found that OPC are a cellular origin of oligodendrogliomas, a class of progressive brain tumors with OPC-features. We provide mechanistic insights explaining how the proteoglycan NG2 participates in a cell fate switch in dividing OPC to generate a one-to-one ratio of self-renewing and differentiating progeny. Our data suggest that asymmetric cell divisions maintain homeostasis in the postnatal oligodendrocyte lineage and brain. In contrast, we detected loss of asymmetric division as an early defect that distinguishes NG2+ glioma precursors and glioma cells from non-neoplastic NG2+ OPC. We currently study whether loss of asymmetric cell division is causal to the neoplastic transformation of oligodendrocyte progenitors (OPC). In addition, we address whether re-storing normal rates of asymmetric cell division asymmetry-defective OPC limits their tumor-initiating capacities.
A neural stem cell foundation of pediatric malignant astrocytomas
We have recently developed an endogenous mouse model, which faithfully recapitulates two genetic alterations found together in a subset of pediatric malignant astrocytomas (PMA) patients. For this purpose, we used transgenics developed by Dr. McMahon at UCSF to specifically activate in neural stem cells and their progeny the activating point mutation within BRaf, BRafV600E, and homozygous deletion of the tumor suppressor and cell cycle regulator CDKN2A, using a virus-based approach. In collaboration with other UCSF stem cell researchers, including Dr. Rowitch and Alvarez-Buylla, we are in the process to narrowly define the cellular origin of pediatric malignant astrocytomas (PMA), determine neuroanatomical and temporal aspects of BRafV600E – induced PMA and identify cellular defects associated with BRafV600E-mediated cellular transformation.
In collaboration with other Brain Tumor Research Center investigators such as Dr. Costello, we have established a panel of 35 patient-derived cultures from low-grade and high-grade gliomas. These cells are used for distinct purposes and my lab in particular investigates cellular hierarchies as a potential underlying mechanism for tumor cell heterogeneity in high-grade gliomas.