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Randall S Johnson PhD

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Professor of Molecular Physiology and Pathology, Wellcome Trust Principal Research Fellow
Tel: +44 (0)1223 765931, E-mail: rsj33@cam.ac.uk

Our laboratory uses genetic models to study the effects of hypoxia in physiological and pathological contexts, specifically dissecting the roles of different isoforms of Hypoxia Inducible Factors (HIF) as regulators of the hypoxia response in different cell types.

Cancer
One of the functions of the mammalian hypoxic response in development and cancer is the generation of nascent vascular networks through angiogenesis. Through transcriptional regulation of the vascular endothelial growth factor A (VEGF-A) and other angiogenic factors, the Hypoxia-Inducible Factors can increase angiogenesis in an oxygen dependent fashion, and gives a survival and growth advantage to HIF wild type tumors. However, their role in other cell types is not always redundant. We are starting to understand that each cell type within the tumor microenvironment has specific hypoxia response strategies that independently affect tumor growth and tumor dispersion. We use genetic techniques to identify the role of hypoxia-triggered and HIF-dependent responses in different cell types, in cancer and other pathologies.

Inflammation
The complex nature of the link between inflammation and cancer has been debated in the scientific literature. Studies conducted in our lab determined the essential role of HIF-1α in mounting a full inflammatory response in myeloid cells. Further studies showed that HIF-1α deficient myeloid cells have defects in the intracellular killing of phagocytosed bacteria. We have also shown that HIF and hypoxia-regulated responses in inflammatory cells have striking effects on both inflammatory cell function and cancer progression. We continue to use genetic strategies to determine the role of HIF-1α in inflammation and the contribution this has both to inflammation and infectivity as well as to models of cancer.

Physiology
An essential role for HIF in physiology is the maintenance of whole body oxygen delivery systems and responses. We are investigating the roles of this pathway in regulating diverse physiologies including erythropoiesis, ventilatory response, and metabolism.

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Lab members
Dr Cristina Branco-Price, Research Associate
Dr Andrew Cowburn, Senior Research Associate
Dr Colin Evans, Research Associate
Dr Asis Palazon, Research Associate
Dr Hideki Yamamoto, Research Associate

Selected publications
Evans CE, Branco-Price C, Johnson RS. HIF-mediated endothelial response during cancer progression. Int J Hematol. 2012 May;95(5):471-7. Epub 2012 May 8. PubMed PMID: 22562456.

Kim JW, Evans C, Weidemann A, Takeda N, Lee YS, Stockmann C, Branco-Price C, Brandberg F, Leone G, Ostrowski MC, Johnson RS. Loss of Fibroblast HIF-1α Accelerates Tumorigenesis. Cancer Res. 2012 Jul 1;72(13):3187-3195. Epub 2012 May 3. PubMed PMID: 22556263.

Branco-Price C, Zhang N, Schnelle M, Evans C, Katschinski DM, Liao D, Ellies L, Johnson RS. Endothelial cell HIF-1α and HIF-2α differentially regulate metastatic success. Cancer Cell. 2012 Jan 17;21(1):52-65. PubMed PMID: 22264788; PubMed Central PMCID: PMC3334270.

Keith B, Johnson RS, Simon MC. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2011 Dec 15;12(1):9-22. doi: 10.1038/nrc3183. Review. PubMed PMID: 22169972.

Stockmann C, Kirmse S, Helfrich I, Weidemann A, Takeda N, Doedens A, Johnson RS. A wound size-dependent effect of myeloid cell-derived vascular endothelial growth factor on wound healing. J Invest Dermatol. 2011 Mar;131(3):797-801. Epub 2010 Nov 25. PubMed PMID: 21107350.

Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, Coussens LM, Karin M, Goldrath AW, Johnson RS. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res. 2010 Oct 1;70(19):7465-75. Epub 2010 Sep 14. PubMed PMID: 20841473; PubMed Central PMCID: PMC2948598.

Rundqvist H, Johnson RS. Hypoxia and metastasis in breast cancer. Curr Top Microbiol Immunol. 2010;345:121-39. Review. PubMed PMID: 20549469.

Weidemann A, Krohne TU, Aguilar E, Kurihara T, Takeda N, Dorrell MI, Simon MC, Haase VH, Friedlander M, Johnson RS. Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina. Glia. 2010 Aug;58(10):1177-85. PubMed PMID: 20544853; PubMed Central PMCID: PMC2993327.

Branco-Price C, Johnson RS. Tumor vessels are Eph-ing complicated. Cancer Cell. 2010 Jun 15;17(6):533-4. PubMed PMID: 20541698.

Zhang N, Fu Z, Linke S, Chicher J, Gorman JJ, Visk D, Haddad GG, Poellinger L, Peet DJ, Powell F, Johnson RS. The asparaginyl hydroxylase factor inhibiting HIF-1α is an essential regulator of metabolism. Cell Metab. 2010 May 5;11(5):364-78. Epub 2010 Apr 15. PubMed PMID: 20399150; PubMed Central PMCID: PMC2893150.

Seagroves TN, Peacock DL, Liao D, Schwab LP, Krueger R, Handorf CR, Haase VH, Johnson RS. VHL deletion impairs mammary alveologenesis but is not sufficient for mammary tumorigenesis. Am J Pathol. 2010 May;176(5):2269-82. Epub 2010 Apr 9. PubMed PMID: 20382704; PubMed Central PMCID: PMC2861092.

Takeda N, O'Dea EL, Doedens A, Kim JW, Weidemann A, Stockmann C, Asagiri M, Simon MC, Hoffmann A, Johnson RS. Differential activation and antagonistic function of HIFα isoforms in macrophages are essential for NO homeostasis. Genes Dev. 2010 Mar 1;24(5):491-501. PubMed PMID: 20194441; PubMed Central PMCID: PMC2827844.

Stockmann C, Kerdiles Y, Nomaksteinsky M, Weidemann A, Takeda N, Doedens A, Torres-Collado AX, Iruela-Arispe L, Nizet V, Johnson RS. Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4329-34. Epub 2010 Feb 8. PubMed PMID: 20142499; PubMed Central PMCID: PMC2840078.

Weidemann A, Kerdiles YM, Knaup KX, Rafie CA, Boutin AT, Stockmann C, Takeda N, Scadeng M, Shih AY, Haase VH, Simon MC, Kleinfeld D, Johnson RS. The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice. J Clin Invest. 2009 Nov;119(11):3373-83. doi: 10.1172/JCI39378. Epub 2009 Oct 5. PubMed PMID: 19809162; PubMed Central PMCID: PMC2769183.

Nizet V, Johnson RS. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol. 2009 Sep;9(9):609-17. Review. PubMed PMID: 19704417.

Kim JW, Johnson RS. You don't need a PHD to grow a tumor. Dev Cell. 2009 Jun;16(6):781-2. PubMed PMID: 19531349.

Stockmann C, Doedens A, Weidemann A, Zhang N, Takeda N, Greenberg JI, Cheresh DA, Johnson RS. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature. 2008 Dec 11;456(7223):814-8. Epub 2008 Nov 9. PubMed PMID: 18997773; PubMed Central PMCID: PMC3103772.

Weidemann A, Johnson RS. Nonrenal regulation of EPO synthesis. Kidney Int. 2009 Apr;75(7):682-8. Epub 2009 Jan 21. Review. PubMed PMID: 19165176.

Peyssonnaux C, Boutin AT, Zinkernagel AS, Datta V, Nizet V, Johnson RS. Critical role of HIF-1α in keratinocyte defense against bacterial infection. J Invest Dermatol. 2008 Aug;128(8):1964-8. Epub 2008 Mar 6. PubMed PMID: 18323789.

Lei L, Mason S, Liu D, Huang Y, Marks C, Hickey R, Jovin IS, Pypaert M, Johnson RS, Giordano FJ. Hypoxia-inducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein. Mol Cell Biol. 2008 Jun;28(11):3790-803. Epub 2008 Feb 19. PubMed PMID: 18285456; PubMed Central PMCID: PMC2423296.