title: Targeting the cytosolic innate immune receptors RIG-I and MDA5 effectively counteracts cancer cell heterogeneity in glioblastoma.
abstract: Cellular heterogeneity, for example, the intratumoral coexistence of cancer cells with and without stem cell characteristics, represents a potential root of therapeutic resistance and a significant challenge for modern drug development in glioblastoma (GBM). We propose here that activation of the innate immune system by stimulation of innate immune receptors involved in antiviral and antitumor responses can similarly target different malignant populations of glioma cells. We used short-term expanded patient-specific primary human GBM cells to study the stimulation of the cytosolic nucleic acid receptors melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). Specifically, we analyzed cells from the tumor core versus "residual GBM cells" derived from the tumor resection margin as well as stem cell-enriched primary cultures versus specimens without stem cell properties. A portfolio of human, nontumor neural cells was used as a control for these studies. The expression of RIG-I and MDA5 could be induced in all of these cells. Receptor stimulation with their respective ligands, p(I:C) and 3pRNA, led to in vitro evidence for an effective activation of the innate immune system. Most intriguingly, all investigated cancer cell populations additionally responded with a pronounced induction of apoptotic signaling cascades revealing a second, direct mechanism of antitumor activity. By contrast, p(I:C) and 3pRNA induced only little toxicity in human nonmalignant neural cells. Granted that the challenge of effective central nervous system (CNS) delivery can be overcome, targeting of RIG-I and MDA5 could thus become a quintessential strategy to encounter heterogeneous cancers in the sophisticated environments of the brain.
authors: Stem Cell Pathologies, University of Bonn Medical Center, Bonn, Germany. martin.glas@ukb
authors: Martin
authors: M
authors: Glas
authors: Christoph
authors: C
authors: Coch
authors: Daniel
authors: D
authors: Trageser
authors: Juliane
authors: J
authors: Dassler
authors: Matthias
authors: M
authors: Simon
authors: Philipp
authors: P
authors: Koch
authors: Jerome
authors: J
authors: Mertens
authors: Tamara
authors: T
authors: Quandel
authors: Raphaela
authors: R
authors: Gorris
authors: Roman
authors: R
authors: Reinartz
authors: Anja
authors: A
authors: Wieland
authors: Marec
authors: M
authors: Von Lehe
authors: Annette
authors: A
authors: Pusch
authors: Kristin
authors: K
authors: Roy
authors: Martin
authors: M
authors: Schlee
authors: Harald
authors: H
authors: Neumann
authors: Rolf
authors: R
authors: Fimmers
authors: Ulrich
authors: U
authors: Herrlinger
authors: Oliver
authors: O
authors: Brüstle
authors: Gunther
authors: G
authors: Hartmann
authors: Robert
authors: R
authors: Besch
authors: Björn
authors: B
authors: Scheffler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003600:Cytosol / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000072640:Interferon-Induced Helicase, IFIH1; D008024:Ligands; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D011971:Receptors, Immunologic; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1