Kevin Ryan - Tumour Cell Death

Introduction

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The aim of our group is to understand the factors regulating programmed cell death in cancer cells. Since it is known that inhibition of cell death mechanisms is a common event in tumour development, this poses problems for many forms of chemotherapy that utilise cell death pathways, leading to drug resistance.

We are investigating both known cell death regulators as well as searching for novel proteins that control cell death and chemosensitivity. We envisage that the knowledge gained from our studies will be translated and lead to the improvement of existing clinical regimens or new targets for therapeutic intervention.

Lab Report

Key Publications

Rosenfeldt MT, O'Prey J, Morton JP, Nixon C, Mackay G, Mrowinska A, Au A, Rai TS, Zheng L, Ridgway R, Adams PD, Anderson KI, Gottlieb E, Sansom OJ, Ryan KM. p53 status determines the role of autophagy in pancreatic tumour development. Nature 2013. Epub 2013/12/07.

Long JS, Crighton D, O’Prey J, MacKay G, Zheng L, Palmer TM, Gottlieb E, Kevin M. Ryan KM. Extracellular adenosine sensing - a metabolic cell death priming mechanism downstream of p53. Molecular Cell 50: 394-406, 2013

Mah L-Y, Ryan KM. Autophagy and Cancer. Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a008821, published online 13 Dec 2011

Wilkinson S, O'Prey J, Fricker M, Ryan KM. Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity. Genes Dev 23: 1283-8, 2009

Bell HS, Dufes C, O'Prey J, Crighton D, Bergamaschi D, Lu X, Schätzlein AG, Vousden KH, Ryan KM. A novel p53-derived apoptotic peptide de-represses p73 to cause tumor regression in vivo. J Clin Invest 117: 1008-18, 2007

Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM. DRAM – a p53- induced modulator of autophagy is critical for apoptosis. Cell 126: 121-34, 2006

Biography

Education and qualifications

1996: PhD, Beatson Institute(University of Glasgow), Supervisor George Birnie
1991: BSc, Biochemistry (Honours), University of Liverpool

Appointments

2007-present: Professor of Molecular Cell Biology, University of Glasgow
2007-present: Senior Group Leader, CRUK Beatson Institute
2002-2008: Cancer Research UK Senior Cancer Research Fellow
2001-2007: Junior Group Leader, CRUK Beatson Institute
1996-2001: Postdoctoral Fellow with Karen Vousden, National Cancer Institute, Frederick, USA

Honours and awards

Fellow of the Royal Society of Edinburgh, 2016
Tenovus Medal, 2012
Cancer Researcher Award, European Association for Cancer Research, 2010
Elected Fellow of the Society of Biology, 2009
Certificate of Merit, European Association for Cancer Research, 2002
Cancer Research UK Senior Cancer Research Fellowship, 2002
National Institutes of Health Year 2001 Fellows Award for Research Excellence, 2000
National Institutes of Health Year 2000 Fellows Award for Research Excellence, 1999

Recent Publications

2016

Baudot AD, Crighton D, O'Prey J, Somers J, Sierra Gonzalez P, Ryan KM (2016) p53 directly regulates the glycosidase FUCA1 to promote chemotherapy-induced cell death. Cell Cycle 15: 2299-308

Gillespie DA, Ryan KM (2016) Autophagy is critically required for DNA repair by homologous recombination. Mol Cell Oncol 3: e1030538

Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K, Adhihetty PJ, Adler SG, Agam G, Agarwal R, Aghi MK, Agnello M, Agostinis P,Aguilar PV, Aguirre-Ghiso J, Airoldi EM et al. (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12: 1-222

Mrschtik M, Ryan KM (2016) Another DRAM involved in autophagy and cell death. Autophagy 12: 603-5

Patella F, Neilson LJ, Athineos D, Erami Z, Anderson KI, Blyth K, Ryan KM, Zanivan S (2016) In-Depth Proteomics Identifies a Role for Autophagy in Controlling Reactive Oxygen Species MediatedEndothelial Permeability. Journal of proteome research 15: 2187-97

Sakamaki J, Ryan KM (2016) Autophagy Determines the Path on the TRAIL to Death. Developmental cell 37: 291-3

2015

Baudot AD, Haller M, Mrschtik M, Tait SW, Ryan KM. Using enhanced-mitophagy to measure autophagic flux. Methods 75: 105-11, 2015

Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH, Cecconi F, Codogno P, Debnath J, Gewirtz DA, Karantza V, Kimmelman A, Kumar S, Levine B, Maiuri MC, Martin SJ, Penninger J, Piacentini M, Rubinsztein DC, Simon HU, Simonsen A, Thorburn AM, Velasco G, Ryan KM, Kroemer G. Autophagy in malignant transformation and cancer progression. EMBO J 34: 856-80, 2015

Graczyk D, White RJ, Ryan KM. Involvement of RNA Polymerase III in Immune Responses. Mol Cell Biol 35: 1848-59, 2015

Liu EY, Xu N, O'Prey J, Lao LY, Joshi S, Long JS, O'Prey M, Croft DR, Beaumatin F, Baudot AD, Mrschtik M, Rosenfeldt M, Zhang Y, Gillespie DA, Ryan KM. Loss of autophagy causes a synthetic lethal deficiency in DNA repair. Proc Natl Acad Sci U S A 112: 773-8, 2015

Long JS, Schoonen PM, Graczyk D, O'Prey J, Ryan KM. p73 engages A2B receptor signalling to prime cancer cells to chemotherapy-induced death. Oncogene 2015. Epub 2015/02/11

Mrschtik M, O'Prey J, Lao LY, Long JS, Beaumatin F, Strachan D, O'Prey M, Skommer J, Ryan KM. DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose. Cell Death Differ 2015. Epub 2015/05/02

Mrschtik M, Ryan KM. Lysosomal proteins in cell death and autophagy. FEBS J 2015; 282: 1858-70. Epub 2015/03/05. 25735653

2014

Haller M, Hock AK, Giampazolias E, Oberst A, Green DR, Debnath J, Ryan KM, Vousden KH, Tait SWG. Ubiquitination and proteasomal degradation of ATG12 regulates its pro-apoptotic activity, Autophagy 10: 2269-78, 2014

Joshi S, Ryan KM. Autophagy chews Fap to promote apoptosis. Nat Cell Biol 16: 23-5, 2014

Rosenfeldt MT, Bell LA, Long JS, O'Prey J, Nixon C, Roberts F, Dufes C, Ryan KM. E2F1 drives chemotherapeutic drug resistance via ABCG2. Oncogene 33: 4164-72, 2014

2013

Rosenfeldt MT, O'Prey J, Morton JP, Nixon C, Mackay G, Mrowinska A, Au A, Rai TS, Zheng L, Ridgway R, Adams PD, Anderson KI, Gottlieb E, Sansom OJ, Ryan KM. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504: 296-300, 2013

Long JS, Crighton D, O’Prey J, MacKay G, Zheng L, Palmer TM, Gottlieb E, Kevin M. Ryan KM. Extracellular adenosine sensing - a metabolic cell death priming mechanism downstream of p53. Molecular Cell 50: 394-406, 2013

Rosenfeldt MT, Bell LA, Long JS, O'Prey J, Nixon C, Roberts F, Dufes C, Ryan KM. E2F1 drives chemotherapeutic drug resistance via ABCG2. Oncogene 2013. Epub 2013/11/28.

Macintosh RL, Ryan KM. Autophagy in tumour cell death. Semin Cancer Biol 23: 344-51, 2013

Helgason GV, Holyoake TL, Ryan KM. Role of autophagy in cancer prevention, development and therapy. Essays Biochem 2013; 55: 133-51. Epub 2013/09/28.

Bennett HL, Stockley J, Fleming JT, Mandal R, O'Prey J, Ryan KM, Robson CN, Leung HY. Does androgen-ablation therapy (AAT) associated autophagy have a pro-survival effect in LNCaP human prostate cancer cells? BJU Int 111(4): 672-82, 2013

Laine A, Sihto H, Come C, Rosenfeldt M, Zwolinska A, Niemelä M, Khanna A, Chan EK, Kähäri V-M, Kellokumpu-Lehtinen P-L, Sansom OJ, Evan GI, Junttila M, Ryan KM, Marine J-C, Joensuu H, Westermarck J. Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1. Cancer Discovery 3(2): 182-197, 2013

Ramirez-Peinado S, Leon-Annicchiarico CL, Galindo-Moreno J, Iurlaro R, Caro-Maldonado A, Prehn JH, Ryan KM, Munoz-Pinedo C. Glucose-starved Cells Do Not Engage in Prosurvival Autophagy. J Biol Chem 288: 30387-98, 2013

2012

Macintosh RL, Timpson P, Thorburn J, Anderson KI, Thorburn A, Ryan KM. Inhibition of autophagy impairs tumor cell invasion in an organotypic model. Cell Cycle 11: 2022-9, 2012

Mah L-Y, O’Prey J, Baudot AD, Hoekstra A, Ryan KM. DRAM-1 encodes multiple isoforms that regulate autophagy. Autophagy 8: 1-11, 2012

Rosenfeldt M, Nixon C, Liu E, Mah LY, Ryan KM. Analysis of macroautophagy by immunohistochemistry. Autophagy 8(6): 963-9, 2012

Liu EY, Ryan KM. Autophagy and cancer - issues we need to digest. J Cell Sci 125: 2349-58, 2012

Long JS, Ryan KM. New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy. Oncogene 31(49): 5045-60, 2012

Ladoire S, Chaba K, Martins I, Sukkurwala AQ, Adjemian S, Michaud M, Poirier-Colame V, Andreiuolo F, Galluzzi L, White E, Rosenfeldt M, Ryan KM, Zitvogel L, Kroemer G. Immunohistochemical detection of cytoplasmic LC3 puncta in human cancer specimens. Autophagy 8(8): 1175-84, 2012

Lemarié F, Croft DR, Tate RJ, Ryan KM, Dufès C. Tumor regression following intravenous administration of a tumor-targeted p73 gene delivery system. Biomaterials 33(9): 2701-9, 2012

Klionsky DJ, Ryan KM et al. Guidelines for the use and interpretation of assays to monitor autophagy. Autophagy 8(4): 445-544, 2012

2011

Wilkinson S, Croft DR, O'Prey J, Meedendorp A, O'Prey M, Dufes C, Ryan KM (2011). The cyclin-dependent kinase PITSLRE/CDK11 is required for successful autophagy. Autophagy 7. [Epub ahead of print].

Baudot AD, Ryan KM. p53 and tumor surveillance: Killer finds way to recruit assassins. Cell Cycle 2011; 10: 3818

Mah L-Y, Ryan KM. Autophagy and Cancer. Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a008821, published online 13 Dec 2011

Rosenfeldt MT, Ryan KM (2011). The multiple roles of autophagy in cancer. Carcinogenesis 32, 955-63.

Stindt MH, Carter S, Vigneron AM, Ryan KM, Vousden KH. MDM2 promotes SUMO-2/3 modification of p53 to modulate transcriptional activity. Cell Cycle 2011; 10: 3176-88

2010

Fricker M, O'Prey J, Tolkovsky AM, Ryan KM (2010). Phosphorylation of Puma modulates its apoptotic function by regulating protein stability. Cell Death Dis. 1, e59.

Helgason GV, O'Prey J, Ryan KM (2010). Oncogene-induced sensitization to chemotherapyinduced death requires induction as well as deregulation of E2F1. Cancer Res. 70, 4074-80.

O'Prey J, Crighton D, Martin AG, Vousden KH, Fearnhead HO, Ryan KM (2010). p53-mediated induction of Noxa and p53AIP1 requires NFkappaB. Cell Cycle 9, 947-52.

Bennett H, Fleming J, O’Prey J, Ryan KM, Leung H (2010). Androgens modulate autophagy and cell death via regulation of the ER chaperone Grp78/BiP in prostate cancer cells. Cell Death Dis. 1, e72.

Croft DR, Crighton D, Samuel MS, Lourenco FC, Munro J, Wood J, Bensaad K, Vousden KH, Sansom OJ, Ryan KM, Olson MF (2010). p53-mediated transcriptional regulation and activation of the actin cytoskeleton regulatory RhoC to LIMK2 signaling pathway promotes cell survival. Cell Res. 21, 666-82.

Long JS, Ryan KM (2010). p53 and senescence: a little goes a long way. Cell Cycle 9, 4050-1.

Lorin S, Pierron G, Ryan KM, Codogno P, Djavaheri-Mergny M (2010). Evidence for the interplay between JNK and p53-DRAM signalling pathways in the regulation of autophagy. Autophagy 6, 153-4.

Ryan KM (2010). Cancer: Viruses' backup plan. Nature 466, 1054-5.

Ryan KM (2010). p53 and autophagy in cancer: guardian of the genome meets guardian of the proteome. Eur J Cancer 47, 44-50.

Wilkinson S, Ryan KM (2010). Autophagy: an adaptable modifier of tumourigenesis. Curr Opin Genet Dev. 20, 57-64.

Lab Members

Ryan Team 2012

Post-docs

Florian Beaumatin
Jaclyn Long (Worldwide Cancer Research)
Jun-ichi Sakamak
Barbara Zunino

Scientific Officer

Jim O'Prey

PhD Students

Valentin Barthet
Pablo Sierra-Gonzalez

Research

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Seminars

Beatson Institute Seminars

Find out more about our seminars including our Distinguished Seminar Programme.

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