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Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis

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/β-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-1α, 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-1α 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.

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Acknowledgements

Research in the Cramer lab was supported by grants from Deutsche Krebshilfe (109160) and Deutsche Forschungsgemeinschaft (CR 133/2-1 until 2–4). NR was supported by a grant from the BMBF (MAPTor-NET (031A426A)). We are indebted to Ralf Weiskirchen (University Hospital Aachen) for help regarding the MLEC assay. We are grateful to Christine Sers (Charité, Berlin) and Florian R. Greten (Georg-Speyer-Haus, Frankfurt) for helpful discussions and to Ilia N. Buhtoiarov (Children’s Hospital of New Jersey, USA), Glenn S. Belinsky, Daniel W. Rosenberg (University of Connecticut Health Center, Farmington, USA), and Takuji Tanaka (Gifu Municipal Hospital, Japan) for providing control reagents. We are grateful to Deborah Gumucio (University of Michigan, USA) for providing Villin-Cre mice. The excellent technical assistance of Birgit Bogdanoff and Simone Spiekermann is highly appreciated. Parts of this work were granted the “Best Poster Award” at the 2015 CELL symposium “Cancer, Inflammation and Immunity” in Sitges, Spain.

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Conceptualization, NR, MM, and TC; methodology, NR, ME, SJ, AE, KTW, AAK, AF, SN, MG, IR, T.E., CZ, SK, RH, MBM, WF, and MM; formal analysis, investigation, and visualization, NR, ME, SJ, AE, AAK, RK, SN, IR, MG, CZ, SK, MBM, MM, and TC; writing, NR, FT, MM, and TC; supervision, resources, and funding acquisition, RK, SK, CEL, WB, MS, LS, OS, FT, MM, and TC; project administration, TC.

Correspondence to Thorsten Cramer.

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