Petritsch Laboratory
The Petritsch Lab studies the basic properties of normal neural stem cells and glial progenitors such as self-renewal, differentiation and asymmetric cell division. In mouse models, we determine how these properties change as neural stem cells and glial progenitor become mutated and turn into glioma precursor and glioma cells. In addition, we critically evaluate the cancer stem cell hypothesis which proposes that aggressive brain tumors, such as glioblastomas, grow from therapy-resistant, stem cell-like subpopulations through hierarchical divisions. The goal of our studies is to define points of disruption in glioma precursors and glioma cells to which effective anti-glioma therapies can be targeted.
The Petritsch lab analyzes premalignant and malignant murine neural stem cells and glial progenitors in cell culture and in vivo. We have developed specialized assays to study mechanism of asymmetric cell division and cell fate determination on a single cell level in vitro and in vivo. In addition, we develop and utilize glioma models based on stem and progenitor cells in preclinical testing of novel therapies in collaboration with other UCSF researchers and biotech companies. In a collaborative effort, Brain Tumor Research Center investigators establish panels of patient-derived cultures from low-grade and high-grade gliomas.
Current Research Projects
Asymmetry-defective oligodendrocyte progenitors are oligodendroglioma precursors
NG2+ oligodendrocyte progenitors (OPC) can be a cellular origin of murine oligodendrogliomas and NG2+ oligodendroglioma cells have high tumor-initiating potential. To better understand the ill-defined mechanisms for neoplastic transformation, we investigated the mode by which murine and human OPC divide to self-renew and differentiate. We found that postnatal OPC self-renew and generate mature oligodendrocytes by undergoing asymmetric cell divisions. We provided first 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. 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. Our bioinformatic approach to existing glioma databases revealed that 12 out of 30 conserved asymmetry regulators are misexpressed in human oligodendrogliomas. Our data suggest that asymmetric cell divisions maintain homeostasis in the postnatal oligodendrocyte lineage and brain and that losing asymmetric cell division might cause tumor initiation. We are currently investigating whether loss of asymmetric cell division causes the neoplastic transformation of oligodendrocyte progenitors (OPC) using in vivo models, specialized cell culture assays and bioinformatic approaches. In addition we test 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
Astrocytomas are gliomas with astrocytic features, which are less sensitive to standard therapies then oligodendrogliomas. The aggressive growth of adult has in part been attributed to their stem cell foundation. To determine the neuro-developmental aspect of pediatric astrocytomas, we have recently developed an endogenous mouse model, which faithfully recapitulates genetic alterations found together in a subset of pediatric malignant astrocytomas (PMA) patients. We use transgenic mice developed 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. In collaboration with other UCSF stem cell researchers 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.
Hierarchical divisions of tumor-initiating cells as underlying mechanism for tumor cell heterogeneity
The cancer stem cell hypothesis proposes that only the tumor-initiating cells (TIC) at the top of a cellular hierarchy are therapy-resistant and malignant when injected in mice. We hypothesize that tumor cells establish hierarchy through asymmetric divisions. We have yet to demonstrate that TIC similar to neural stem cells generate hierarchical cells with distinct phenotypes, malignant potential and therapy responsiveness, by dividing asymmetrically. A hierarchical model potentially could explain the heterogeneity observed in glioblastomas and if confirmed has important implications for therapies. Using specialized cell culture assays, the pair assays, and life imaging, we define whether TIC from different glioma types have different rates of asymmetrical divisions. Using FACS we isolate pure subpopulations and subject them to cell culture assays to investigate the link of asymmetrical divisions, tumor cell hierarchy and heterogeneity. Taken together, we critically evaluate the cancer stem cell hypothesis. For these studies we mainly employ human primary tumor cells and aim to identify the tumor subpopulation responsible for tumor maintenance and therapy resistance.