SP 6

Molecular oxygen sensing and PHD-inhibition: Implications for colorectal cancer growth

Adaptive responses to oxygen deprivation (hypoxia) are mediated by hypoxia inducible transcription factors (HIFs). HIFs affect cancer growth by altering the expression of numerous target genes involved in tumor cell survival, proliferation, metabolism, angiogenesis and metastasis. HIF prolyl hydroxylase enzymes (PHD1, PHD2 and PHD3) are molecular oxygen sensors that regulate the activity of HIFs. Since these PHD enzymes can be inhibited applying pharmacological inhibitors, they are potential therapeutic targets. Specifically, current insight suggests that PHD-inhibition may improve liver function following major hepatectomy, which represents a cornerstone in the clinical management of colorectal liver metastases. However, the specific in vivo functions of PHD1, PHD2 and PHD3 in the growth and metastasis of colorectal tumors remain enigmatic.

This subproject aims at studying the implications of PHD1, PHD2 and PHD3 in local colorectal cancer growth and in the formation of distant colorectal metastases. On the one hand, we are correlating the expression of PHD1, PHD2 and PHD3 in clinical colorectal cancer samples with histopathologic features and clinical outcome. Furthermore, we are applying genetic gain and loss of function approaches in order to study the functional relevance of each PHD enzyme in the tumor cells, as well as in the host tissue at the tumor invasion front. Furthermore, in order to assess how these insights translate to potential applications of pharmacologic PHD-inhibition in colorectal cancer patients, we are assessing the effects of pharmacologic PHD-inhibition on the expansion of colorectal liver metastases, particularly in the setting of surgical liver resection.

With these studies, we aim to exploit the molecular oxygen-sensing pathway in order to develop novel indicators of prognosis and novel therapeutic strategies against colorectal cancer disease.

Team SP6:
PD Dr. med. M. Schneider, Dr. sc. hum. J. Kiss, Dr. med. J. Harnoß, M. Neumann, P. Radhakrishnan, M. Stauch, N. Ruh

from the left to the right: M. Stauch, M. Neumann, PD Dr. med. M. Schneider, Dr. sc. hum. J. Kiss, P. Radhakrishnan, MSc, M. Mollenhauer, MSc

Project-related key publications

Radhakrishnan P, Ruh N, Harnoss JM, Kiss J, Mollenhauer M, Scherr AL, Platzer LK, Schmidt T, Podar K, Opferman JT, Weitz J, Schulze-Bergkamen H, Koehler BC, Ulrich A, Schneider M. Prolyl Hydroxylase 3 Attenuates MCL-1-Mediated ATP Production to Suppress the Metastatic Potential of Colorectal Cancer Cells. Cancer Res. 2016 Apr 15;76(8):2219-30. doi: 10.1158/0008-5472.CAN-15-1474. Epub 2016 Feb 26.

Harnoss JM, Platzer LK, Burhenne J, Radhakrishnan P, Cai J, Strowitzki MJ, Weiss J, Ritter AS, Mollenhauer M, Schmidt T, Ulrich A, Haefeli WE, Schneider M. Prolyl Hydroxylase Inhibition Enhances Liver Regeneration Without Induction of Tumor Growth. Ann Surg. 2016 Mar 8. [Epub ahead of print]

Mollenhauer M, Kiss J, Dudda J, Kirchberg J, Rahbari N, Radhakrishnan P, Niemietz T, Rausch V, Weitz J, Schneider M. Deficiency of the oxygen sensor PHD1 augments liver regeneration after partial hepatectomy. Langenbecks Arch Surg 2012 Dec;397(8):1313-22. doi: 10.1007/s00423-012-0998-5. Epub 2012 Sep 11.

Kiss J, Mollenhauer M, Walmsley SR, Kirchberg J, Radhakrishnan P, Niemietz T, Dudda J, Steinert G, Whyte MKB, Carmeliet P, Mazzone M, Weitz J, Schneider M. Loss of the Oxygen Sensor PHD3 Enhances the Innate Immune Response to Abdominal Sepsis. J Immunol 189:1955-1965 (2012).
This article is featured in the “In This Issue” section of The Journal of Immunology (August 15th issue, 2012), which highlights articles that are among the top 10% of articles published in the Journal. A corresponding ImmunoCast can be found on The Journal of Immunology web site at: http://www.jimmunol.org/rss/jipodcast.xhtml.

Kiss J, Kirchberg J, Schneider M. Molecular oxygen sensing: implications for visceral surgery. Langenbecks Arch Surg March 2012 Apr;397(4):603-10. Epub 2012 Mar 7.

Casazza A, Finisguerra V, Capparuccia L, Camperi A, Swiercz JM, Rizzolio S, Rolny C, Christensen C, Bertotti A, Sarotto I, Risio M, Trusolino L, Weitz J, Schneider M, Mazzone M, Comoglio PM, Tamagnone L. Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J Clin Invest 2010 Aug;120(8):2684-98. doi: 10.1172/JCI42118. Epub 2010 Jul 26.

Walmsley SR, Chilvers ER, Thompson AA, Vaughan K, Marriott HM, Parker LC, Shaw G, Parmar S, Schneider M, Sabroe I, Dockrell DH, Milo M, Taylor CT, Johnson RS, Pugh CW, Ratcliffe PJ, Maxwell PH, Carmeliet P, Whyte MK. Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice. J Clin Invest 2011 Mar;121(3):1053-63. doi: 10.1172/JCI43273. Epub 2011 Feb 7.

Schneider M, van Geyte K, Fraisl P, Kiss J, Aragones J, Mazzone M, Mairbäurl H, DeBock K, Jeoung N, Mollenhauer M, Georgiadou M, Bishop T, Roncal C, Sutherland A, Jordan B, Gallez B, Weitz J, Harris R, Maxwell P, Baes M, Ratcliffe P, Carmeliet P. Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury. Gastroenterology 2010 Mar;138(3):1143-54.e1-2. Epub 2009 Oct 8.

Tambuwala MM, Cummins EP, Lenihan CR, Kiss J, Stauch M, Scholz CC, Fraisl P, Lasitschka F, Mollenhauer M, Saunders SP, Maxwell PH, Carmeliet P, Fallon PG, Schneider M1, Taylor CT1. Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function. Gastroenterology 2010 Dec;139(6):2093-101. Epub 2010 Jun 30. (1These authors contributed equally to this work)

Aragones J1, Schneider M1, van Geyte K1, Fraisl P, Dresselaers T, Mazzone M, Dirkx R, Zacchigna S, Jeoung NH, Lambrechts D, Bishop T, Lafuste P, Diez A, Harten SK, VanNoten P, De Bock K, Willam C, Tjwa M, Grosfeld A, Navet R, Moons L, Wijeyekoon B, Nuyts J, Vermaelen P, Jordan B, Lupu F, Dewerchin M, Pugh C, Salmon P, Mortelmans L, Gallez B, Gorus F, Buyse J, Sluse F, Harris FRA, Gnaiger E, Hespel P, Van Hecke P, Schuit F, Van Veldhoven P, Ratcliffe P, Baes M, Maxwell  P, Carmeliet P. Deficiency or inhibition of oxygen sensor PHD1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet 2008 Feb;40(2):170-80. Epub 2008 Jan 6. 1Contributed equally.

[(Highlighted by editorials and previews in Science (Editors’ choice, Science 2008;319,387), Nature Genetics (D. Kelly, Nat Genet 2008;40,132-134), Cell Metabolism (C. Dang and P. Gao, Cell Metab 2008;7)].

Schneider M and Weitz J. Oxygen deprivation and hypoxia tolerance. Dtsch Med Wochenschr (invited review) 2008;133(42), 2168-2172.

Schneider M, van Geyte K, Fraisl P, Kiss J, Aragones J, Mazzone M, Mairbäurl H, DeBock K, Jeoung N, Mollenhauer M, Georgiadou M, Bishop T, Roncal C, Sutherland A, Jordan B, Gallez B, Weitz J, Harris R, Maxwell P, Baes M, Ratcliffe P, Carmeliet P. Loss or silencing of the PHD1 Prolyl Hydroxylase protects livers of mice against ischemia/reperfusion injury. Gastroenterology 2010 Mar;138(3):1143-54.e1-2. Epub 2009 Oct 8.

Tambuwala MM, Cummins EP, Lenihan CR, Kiss J, Stauch M, Scholz CC, Fraisl P, Lasitschka F, Mollenhauer M, Saunders SP, Maxwell PH, Carmeliet P, Fallon PG, Schneider M1, Taylor CT1. Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function. Gastroenterology 2010 Dec;139(6):2093-101. Epub 2010 Jun 30. (1These authors contributed equally to this work).

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