00085472can182725-sup-207985_2_video_5256471_pks9s9.mov (13.17 MB)
Supplementary Video from Blockade of a Laminin-411–Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk
media
posted on 2023-03-31, 03:02 authored by Tao Sun, Rameshwar Patil, Anna Galstyan, Dmytro Klymyshyn, Hui Ding, Alexandra Chesnokova, Webster K. Cavenee, Frank B. Furnari, Vladimir A. Ljubimov, Ekaterina S. Shatalova, Shawn Wagner, Debiao Li, Adam N. Mamelak, Serguei I. Bannykh, Chirag G. Patil, Jeremy D. Rudnick, Jethro Hu, Zachary B. Grodzinski, Arthur Rekechenetskiy, Vida Falahatian, Alexander V. Lyubimov, Yongmei L. Chen, Lai S. Leoh, Tracy R. Daniels-Wells, Manuel L. Penichet, Eggehard Holler, Alexander V. Ljubimov, Keith L. Black, Julia Y. LjubimovaVideo schematically shows the mechanism of glioblastoma treatment by laminin-411 inhibiting nanobioconjugate
Funding
Health Effects of Air Pollution Foundation
History
ARTICLE 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.Usage metrics
Categories
Keywords
AngiogenesisAngiogenesis inhibitors & stimulatorsCancer PreventionPersonalized cancer preventionCns CancersGliomas, GlioblastomasGene RegulationAntisense control of gene expressionNanoparticle AgentsOncogenes & Tumor SuppressorsProgression, Invasion & MetastasisCell adhesion and extracellular matrix
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC