Gliomas are the most common and deadly brain tumors in adults and can arise from mutant oligodendrocyte progenitors by a largely unknown mechanism. Specific treatments to eliminate these malignant OPC have not been developed, primarily because the underlying mechanisms associated with their malignant transformation are not well understood. The goal of this proposal is to find the underlying causes for malignant transformation of OPC by investigating defects in asymmetric cell division and to test specific pharmacological agents targeted to re-store these defects for their ability to impact tumor growth. We have recently provided first molecular evidence that oligodendrocyte progenitors divide asymmetrically to self-renew and generate mature oligodendrocytes by showing that the transmembrane proteoglycan NG2 distributes asymmetrically during mitosis and thereby promotes activation of epidermal receptor growth factor and self-renewal and prevents differentiation of the NG2+ progeny. Oligodendrocyte progenitors with defective NG2 asymmetry aberrantly self-renew, fail to differentiate and turn into glioma - initiating cells. We hypothesize that losing cellular asymmetry transforms oligodendrocyte progenitor cells, by disrupting self-renewal and differentiation. Our preliminary results indeed show that enforcing a block of asymmetric cell division by removing expression of conserved asymmetry regulator Lethal giant larvae, LGL1, in oligodendrocyte progenitors causes tumor formation. Moreover, pharmacological inhibition of Plk1, a conserved regulator of asymmetric cell division, re-stores NG2 asymmetry in malignant, glioma- initiating cells. Guided by such strong preliminary data, we have three specific aims: In the first aim, we determine whether oligodendrocyte progenitor-specific loss of LGL1 causes NG2-dependent tumor- initiation. To fulfill this aim, we propose to generate oligodendrocyte progenitors and oligodendrocyte progenitor precursor deficient for LGL1 alone and co-deficient for LGL1 and NG2, in mouse models using a CRE-LOX approach. The analysis of tumor formation in these models will enable us to distinguish between NG2-dependent and - independent functions of LGL1 in tumor initiation. In the second aim, we will determine a causal link of loss of LGL1, disrupted NG2 asymmetry and tumor initiation in OPC. We will test LGL1-/- oligodendrocyte progenitors for defects in NG2 asymmetry, self-renewal and differentiation. To link losing LGL1 and NG2 asymmetry to malignant transformation, we will evaluate the malignant potential of LGL1-/- and test whether co-deletion of NG2 ameliorates tumor formation and re-expression of symmetric, ectopic NG2 enhances defects in LGL1-/- OPC. In the third aim, we will investigate the pharmacological modulation of asymmetric cell division for its impact on tumor growth. Our goal is to prove that loss of asymmetric cell division is causal to tumor initiation and thereby evaluate novel therapeutic approaches that re-store asymmetric cell division to malignant progenitors and for their potential to impact tumor growth.

Public Health Relevance

Oligodendrogliomas are glioma brain tumors in adults which - despite initial response to conventional therapy - frequently progress and lead to the patient's death. This study addresses an important aspect of human health, of whether restoring normal asymmetric cell division in oligodendrocyte progenitors can prevent tumor initiation. The proposed research is a paradigm for understanding the role of asymmetric cell divisions in all cancers and is relevant to the NIH's mission in its have far-reaching therapeutic impact.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA164746-02
Application #
8400416
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Watson, Joanna M
Project Start
2011-12-13
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$301,353
Indirect Cost
$106,303
Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Andor, Noemi; Graham, Trevor A; Jansen, Marnix et al. (2016) Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nat Med 22:105-13
Olow, Aleksandra; Mueller, Sabine; Yang, Xiaodong et al. (2016) BRAF Status in Personalizing Treatment Approaches for Pediatric Gliomas. Clin Cancer Res 22:5312-5321
Grossauer, Stefan; Koeck, Katharina; Murphy, Nicole E et al. (2016) Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model. Oncotarget 7:75839-75853
Lerner, Robin G; Grossauer, Stefan; Kadkhodaei, Banafsheh et al. (2015) Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating Cells. Cancer Res 75:5355-66
Bakhoum, Samuel F; Kabeche, Lilian; Wood, Matthew D et al. (2015) Numerical chromosomal instability mediates susceptibility to radiation treatment. Nat Commun 6:5990
Lerner, Robin G; Petritsch, Claudia (2014) A microRNA-operated switch of asymmetric-to-symmetric cancer stem cell divisions. Nat Cell Biol 16:212-4
Hashizume, Rintaro; Andor, Noemi; Ihara, Yuichiro et al. (2014) Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 20:1394-6
Gómez-López, Sandra; Lerner, Robin G; Petritsch, Claudia (2014) Asymmetric cell division of stem and progenitor cells during homeostasis and cancer. Cell Mol Life Sci 71:575-97
Andor, Noemi; Harness, Julie V; Müller, Sabine et al. (2014) EXPANDS: expanding ploidy and allele frequency on nested subpopulations. Bioinformatics 30:50-60
Berberoglu, Michael A; Dong, Zhiqiang; Li, Guangnan et al. (2014) Heterogeneously expressed fezf2 patterns gradient Notch activity in balancing the quiescence, proliferation, and differentiation of adult neural stem cells. J Neurosci 34:13911-23

Showing the most recent 10 out of 14 publications