Tissue mechanics promote IDH1-dependent HIF1α-tenascin C feedback to regulate glioblastoma aggression.
Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1α. We found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that our studies attributed to reduced miR-203 suppression of HIF1α and TNC mediated via a tension-dependent positive feedback loop. Thus, our work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status.
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, California 94143, USA.
Yekaterina A
YA
Miroshnikova
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, California 94143, USA.
Janna K
JK
Mouw
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, California 94143, USA.
J Matthew
JM
Barnes
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, California 94143, USA.
Michael W
MW
Pickup
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, California 94143, USA.
Johnathan N
JN
Lakins
Division of Human Biology and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Department of Neurosurgery and Alvord Brain Tumor Center, University of Washington, Seattle, Washington 98109, USA.
Youngmi
Y
Kim
Magnetic Resonance Science Center, Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California 94143, USA.
Khadjia
K
Lobo
Department of Neurology, University of California, San Francisco, California 94143, USA.|Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94158, USA.|Brain Tumor Research Center, Helen Diller Family Cancer Research Center, University of California San Francisco, San Francisco, California 94143, USA.|UCSF Comprehensive Cancer Center, Helen Diller Family Cancer Research Center, University of California San Francisco, San Francisco, California 94143, USA.
Anders I
AI
Persson
Department of Pathology, University of California, San Francisco, California 94143, USA.
Gerald F
GF
Reis
Magnetic Resonance Science Center, Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California 94143, USA.
Tracy R
TR
McKnight
Division of Human Biology and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Department of Neurosurgery and Alvord Brain Tumor Center, University of Washington, Seattle, Washington 98109, USA.
Eric C
EC
Holland
Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94158, USA.|Brain Tumor Research Center, Helen Diller Family Cancer Research Center, University of California San Francisco, San Francisco, California 94143, USA.|UCSF Comprehensive Cancer Center, Helen Diller Family Cancer Research Center, University of California San Francisco, San Francisco, California 94143, USA.|Department of Pathology, University of California, San Francisco, California 94143, USA.
Joanna J
JJ
Phillips
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, California 94143, USA.|Department of Anatomy and Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94143, USA.|Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California 94143, USA.|UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA.
Valerie M
VM
Weaver
D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000378:metabolism; D025461:Feedback, Physiological; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D035683:MicroRNAs / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D019063:Tenascin / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D019063:Tenascin; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human