Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans, distinguished by prominent vascularity and extraordinary vascular abnormality. Most GBM tumors are refractory to conventional cytotoxic therapies. Overgrown, abnormal vasculature characterizes the microenvironment that fuels cancer progression and induces spatially heterogeneous hypoxia and therapeutic resistance in malignant solid tumors. Anti-angiogenic therapies, primarily targeting vascular endothelial growth factor (VEGF)-A and its receptors, have been developed and exploited in recent years; however, the therapeutic benefits are small in GBM, due to acquired treatment resistance and other unidentified mechanisms. Here we show that endothelial cell (EC) plasticity-mediated vascular transformation is critical for aberrant tumor angiogenesis and therapy resistance, therefore serving as a new therapeutic target in GBM. We discover endothelial fibro-transformation (Endo-FT) in GBM vasculature, by which ECs acquire fibroblast phenotypes including high motility and invasiveness to generate excessive abnormal vasculature. Utilizing human specimen and orthotopic, genetic mouse tumor models, our preliminary studies reveal robust Endo-FT in GBM, characterized by EC expression of the mesenchymal markers, and a prominent population of GBM-associated mesenchymal cells with EC origin. Furthermore, our proteomic analysis identifies a critical role of c-Met in Endo-FT, requisite for the vascular abnormality in the GBM microenvironment. c-Met phosphorylation induces matrix metalloproteinase (MMP)-14 expression and Endo-FT. Finally, our in vivo data using EC-specific c-Met knockout mice establish a critical role of c-Met in Endo-FT, cancer growth and progression, and GBM resistance to temozolomide chemotherapy. Based on these results, we hypothesize that Endo-FT is a driving force for aberrant tumor vascularization, and targeting Endo-FT provides a novel strategy to inhibit excessive angiogenesis, normalize tumor vessels, and overcome therapy resistance in GBM. To test this hypothesis, we will 1) determine the in vivo role of c-Met-mediated Endo-FT in tumor hypoxia, glioma progression and therapeutic resistance, and test experiment therapy that combines c-Met inhibition and radiation or chemotherapy in mouse tumor models; 2) define the mechanisms by which HGF/c-Met induces Endo-FT and vascular abnormality with a focus on HGF autocrine and MMP-14 expression; and 3) perform system-wide analysis of the Endo-FT and vascular transformation, focusing on platelet-derived growth factor (PDGF)- and hypoxia-mediated mechanisms. Successful completion of this project may provide alternative insights into aberrant tumor vascularization and lead to development of new anti-angiogenic and vessel normalization strategies for treating GBM.

Public Health Relevance

Glioblastoma multiforme (GBM) is among the most lethal of human malignancies with a current median survival of about 14 months. GBM is distinguished by excessive, abnormal blood vessels, but current anti-vascular therapies targeting the factors that induce vessel formation are not effective in most patients. The goal of this project is to develop new anti-vascular therapies that target cell transformation-mediated vascular abnormalities, which may block tumor progression and overcome GBM resistance to radiation and chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS094533-04
Application #
9534772
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Fountain, Jane W
Project Start
2015-09-30
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wang, Yanling; Xu, Haineng; Liu, Tianrun et al. (2018) Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cells. JCI Insight 3:
Yuan, Jiao; Hu, Zhongyi; Mahal, Brandon A et al. (2018) Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers. Cancer Cell 34:549-560.e9
Liu, Tianrun; Ma, Wenjuan; Xu, Haineng et al. (2018) PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma. Nat Commun 9:3439
Wang, Qirui; He, Zhenqiang; Huang, Menggui et al. (2018) Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2?. Nat Commun 9:559
Lin, Xiaojuan; Shen, Jianfeng; Dan Peng et al. (2018) RNA-binding protein LIN28B inhibits apoptosis through regulation of the AKT2/FOXO3A/BIM axis in ovarian cancer cells. Signal Transduct Target Ther 3:23
Yang, Lu; Zhang, Youyou; Shan, Weiwei et al. (2017) Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition. Sci Transl Med 9:
Zhang, Youyou; He, Qun; Hu, Zhongyi et al. (2016) Long noncoding RNA LINP1 regulates repair of DNA double-strand breaks in triple-negative breast cancer. Nat Struct Mol Biol 23:522-30
Huang, Menggui; Liu, Tianrun; Ma, Peihong et al. (2016) c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma. J Clin Invest 126:1801-14