Fibulin-3 promotes glioma growth and resistance through a novel paracrine regulation of notch signaling

Bin Hu, Mohan S. Nandhu, Hosung Sim, Paula A. Agudelo-Garcia, Joshua C. Saldivar, Claire E. Dolan, Maria E. Mora, Gerard J. Nuovo, Susan E. Cole, Mariano S. Viapiano

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


Malignant gliomas are highly invasive and chemoresistant brain tumors with extremely poor prognosis. Targeting of the soluble factors that trigger invasion and resistance, therefore, could have a significant impact against the infiltrative glioma cells that are a major source of recurrence. Fibulin-3 is a matrix protein that is absent in normal brain but upregulated in gliomas and promotes tumor invasion by unknown mechanisms. Here, we show that fibulin-3 is a novel soluble activator of Notch signaling that antagonizes DLL3, an autocrine inhibitor or Notch, and promotes tumor cell survival and invasion in a Notch-dependent manner. Using a strategy for inducible knockdown, we found that controlled downregulation of fibulin-3 reduced Notch signaling and led to increased apoptosis, reduced self-renewal of glioblastoma-initiating cells, and impaired growth and dispersion of intracranial tumors. In addition, fibulin-3 expression correlated with expression levels of Notch-dependent genes and was a marker of Notch activation in patient-derived glioma samples. These findings underscore a major role for the tumor extracellular matrix in regulating glioma invasion and resistance to apoptosis via activation of the key Notch pathway. More importantly, this work describes a noncanonical, soluble activator of Notch in a cancer model and shows how Notch signaling can be reduced by targeting tumor-specific accessible molecules in the tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)3873-3885
Number of pages13
JournalCancer Research
Issue number15
StatePublished - Aug 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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