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Crister Ceberg

Avdelningschef

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Hypoxia-induced complement component 3 promotes aggressive tumor growth in the glioblastoma microenvironment

Författare

  • Rebecca Rosberg
  • Karolina I. Smolag
  • Jonas Sjölund
  • Elinn Johansson
  • Christina Bergelin
  • Julia Wahldén
  • Vasiliki Pantazopoulou
  • Crister Ceberg
  • Kristian Pietras
  • Anna M. Blom
  • Alexander Pietras
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Summary, in English

Glioblastoma (GBM) is the most aggressive form of glioma with a high rate of relapse despite intensive treatment. Tumor recurrence is tightly linked to radio-resistance, which in turn is associated with hypoxia. Here, we discovered a strong link between hypoxia and local complement signaling using publicly available bulk, single-cell, and spatially resolved transcriptomic data from patients with GBM. Complement component 3 (C3) and the receptor C3AR1 were both associated with aggressive disease and shorter survival in human glioma. In a genetically engineered mouse model of GBM, we found C3 specifically in hypoxic tumor areas. In vitro, we found an oxygen level–dependent increase in C3 and C3AR1 expression in response to hypoxia in several GBM and stromal cell types. C3a induced M2 polarization of cultured microglia and macrophages in a C3aR-dependent fashion. Targeting C3aR using the antagonist SB290157 prolonged survival of glioma-bearing mice both alone and in combination with radiotherapy while reducing the number of M2-polarized macrophages. Our findings establish a strong link between hypoxia and complement pathways in GBM and support a role of hypoxia-induced C3a/C3aR signaling as a contributor to glioma aggressiveness by regulating macrophage polarization.

Avdelning/ar

  • Avdelningen för translationell cancerforskning
  • LUCC: Lunds universitets cancercentrum
  • Proteinkemi, Malmö
  • Medicinsk strålningsfysik, Lund
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publiceringsår

2024-10-08

Språk

Engelska

Publikation/Tidskrift/Serie

JCI Insight

Volym

9

Avvikelse

19

Dokumenttyp

Artikel i tidskrift

Förlag

The American Society for Clinical Investigation

Ämne

  • Cancer and Oncology

Aktiv

Published

Forskningsgrupp

  • Protein Chemistry, Malmö

ISBN/ISSN/Övrigt

  • ISSN: 2379-3708