1. Blockade of a Laminin-411-Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk.
- Author
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Sun T, Patil R, Galstyan A, Klymyshyn D, Ding H, Chesnokova A, Cavenee WK, Furnari FB, Ljubimov VA, Shatalova ES, Wagner S, Li D, Mamelak AN, Bannykh SI, Patil CG, Rudnick JD, Hu J, Grodzinski ZB, Rekechenetskiy A, Falahatian V, Lyubimov AV, Chen YL, Leoh LS, Daniels-Wells TR, Penichet ML, Holler E, Ljubimov AV, Black KL, and Ljubimova JY
- Subjects
- Animals, Apoptosis, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Brain metabolism, Brain pathology, Cell Proliferation, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Glioblastoma metabolism, Humans, Laminin antagonists & inhibitors, Laminin genetics, Mice, Mice, Nude, Neoplastic Stem Cells metabolism, Prognosis, Receptors, Notch genetics, Signal Transduction, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, CRISPR-Cas Systems, Glioblastoma pathology, Laminin metabolism, Nanoparticles chemistry, Neoplastic Stem Cells pathology, Receptors, Notch metabolism, Tumor Microenvironment
- Abstract
There is an unmet need for the treatment of glioblastoma multiforme (GBM). The extracellular matrix, including laminins, in the tumor microenvironment is important for tumor invasion and progression. In a panel of 226 patient brain glioma samples, we found a clinical correlation between the expression of tumor vascular laminin-411 (α4β1γ1) with higher tumor grade and with expression of cancer stem cell (CSC) markers, including Notch pathway members, CD133, Nestin, and c-Myc. Laminin-411 overexpression also correlated with higher recurrence rate and shorter survival of GBM patients. We also showed that depletion of laminin-411 α4 and β1 chains with CRISPR/Cas9 in human GBM cells led to reduced growth of resultant intracranial tumors in mice and significantly increased survival of host animals compared with mice with untreated cells. Inhibition of laminin-411 suppressed Notch pathway in normal and malignant human brain cell types. A nanobioconjugate potentially suitable for clinical use and capable of crossing blood-brain barrier was designed to block laminin-411 expression. Nanobioconjugate treatment of mice carrying intracranial GBM significantly increased animal survival and inhibited multiple CSC markers, including the Notch axis. This study describes an efficient strategy for GBM treatment via targeting a critical component of the tumor microenvironment largely independent of heterogeneous genetic mutations in glioblastoma. Significance: Laminin-411 expression in the glioma microenvironment correlates with Notch and other cancer stem cell markers and can be targeted by a novel, clinically translatable nanobioconjugate to inhibit glioma growth., (©2019 American Association for Cancer Research.)
- Published
- 2019
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