Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis

TY - JOUR

T1 - Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis

AU - Rohwer, Nadine

AU - Jumpertz, Sandra

AU - Erdem, Merve

AU - Egners, Antje

AU - Warzecha, Klaudia T

AU - Fragoulis, Athanassios

AU - Kühl, Anja A

AU - Kramann, Rafael

AU - Neuss, Sabine

AU - Rudolph, Ines

AU - Endermann, Tobias

AU - Zasada, Christin

AU - Apostolova, Ivayla

AU - Gerling, Marco

AU - Kempa, Stefan

AU - Hughes, Russell

AU - Lewis, Claire E

AU - Brenner, Winfried

AU - Malinowski, Maciej B

AU - Stockmann, Martin

AU - Schomburg, Lutz

AU - Faller, William

AU - Sansom, Owen J

AU - Tacke, Frank

AU - Morkel, Markus

AU - Cramer, Thorsten

PY - 2019/7

Y1 - 2019/7

N2 - 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.

AB - 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.

U2 - 10.1038/s41388-019-0816-4

DO - 10.1038/s41388-019-0816-4

M3 - SCORING: Journal article

C2 - 31043706

VL - 38

SP - 5670

EP - 5685

JO - ONCOGENE

JF - ONCOGENE

SN - 0950-9232

IS - 28

ER -