HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice

Nat Commun. 2020 Aug 17;11(1):4111. doi: 10.1038/s41467-020-17873-3.

Rouven Hoefflin ^# ¹, Sabine Harlander ^# ² ³, Silvia Schäfer ¹ ⁴ ⁵, Patrick Metzger ⁵ ⁶, Fengshen Kuo ⁷, Désirée Schönenberger ² ³, Mojca Adlesic ¹ ⁴, Asin Peighambari ¹ ⁴ ⁵, Philipp Seidel ¹ ⁴, Chia-Yi Chen ⁸, Miguel Consenza-Contreras ⁸, Andreas Jud ⁹, Bernd Lahrmann ¹⁰, Niels Grabe ¹⁰, Danijela Heide ¹¹, Franziska M Uhl ¹ ⁵, Timothy A Chan ⁷, Justus Duyster ¹ ¹², Robert Zeiser ¹ ⁴ ¹², Christoph Schell ⁸, Mathias Heikenwalder ¹¹, Oliver Schilling ⁸ ¹² ¹³, A Ari Hakimi ⁷ ¹⁴, Melanie Boerries ⁶ ¹² ¹³, Ian J Frew ¹⁵ ¹⁶ ¹⁷ ¹⁸ ¹⁹ ²⁰

Affiliations

1 Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
2 Institute of Physiology, University of Zurich, Zurich, Switzerland.
3 Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
4 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
5 Faculty of Biology, University of Freiburg, Freiburg, Germany.
6 Institute of Medical Bioinformatics and Systems Medicine, Medical Centre-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
7 Immunogenomics & Precision Oncology Platform (IPOP), Memorial Sloan Kettering Cancer Center, New York, NY, USA.
8 Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
9 Department of General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
10 Hamamatsu Tissue Imaging and Analysis (TIGA) Center, BioQuant, University of Heidelberg, Heidelberg, Germany.
11 Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
12 Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
13 German Cancer Consortium (DKTK), Partner Site Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
14 Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
15 Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. [email protected].
16 Institute of Physiology, University of Zurich, Zurich, Switzerland. [email protected].
17 Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. [email protected].
18 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. [email protected].
19 Faculty of Biology, University of Freiburg, Freiburg, Germany. [email protected].
20 Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. [email protected].
# Contributed equally.

PMID: 32807776 DOI: 10.1038/s41467-020-17873-3

Abstract

Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are required for the clear cell phenotype. Transcriptomic and proteomic analyses reveal that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2α-deficient tumours are characterised by increased antigen presentation, interferon signalling and CD8⁺ T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlate with altered immune microenvironments in human ccRCC. These studies reveal an oncogenic role of HIF-1α in ccRCC initiation and suggest that alterations in the balance of HIF-1α and HIF-2α activities can affect different aspects of ccRCC biology and disease aggressiveness.

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