Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis

Nadine Rohwer, Sandra Jumpertz, Merve Erdem, Antje Egners, Klaudia T. Warzecha, Athanassios Fragoulis, Anja A. Kuehl, Rafael Kramann, Sabine Neuss, Ines Rudolph, Tobias Endermann, Christin Zasada, Ivayla Apostolova, Marco Gerling, Stefan Kempa, Russell Hughes, Claire E. Lewis, Winfried Brenner, Maciej B. Malinowski, Martin StockmannLutz Schomburg, William Faller, Owen J. Sansom, Frank Tacke, Markus Morkel, Thorsten Cramer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Web of Science)

Abstract

The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1's role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/beta-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1 alpha, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1 alpha stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.

Original languageEnglish
Pages (from-to)5670-5685
Number of pages16
JournalOncogene
Volume38
Issue number28
DOIs
Publication statusPublished - 11 Jul 2019

Keywords

  • HYPOXIA-INDUCIBLE FACTOR-1-ALPHA
  • CARCINOMA-ASSOCIATED FIBROBLASTS
  • TUMOR-ASSOCIATED MACROPHAGES
  • TARGETED CANCER-THERAPY
  • DENDRITIC CELLS
  • POOR-PROGNOSIS
  • MURINE MODEL
  • MOUSE MODEL
  • STEM-CELLS
  • FACTOR-I

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