Fibulin-3 promotes glioma growth and resistance through a novel paracrine regulation of Notch signaling.
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.
Department of Neurological Surgery, Dardinger Center for Neuro-Oncology and Neurosciences, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
Bin
B
Hu
Mohan S
MS
Nandhu
Hosung
H
Sim
Paula A
PA
Agudelo-Garcia
Joshua C
JC
Saldivar
Claire E
CE
Dolan
Maria E
ME
Mora
Gerard J
GJ
Nuovo
Susan E
SE
Cole
Mariano S
MS
Viapiano
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D019899:Paracrine Communication / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1