Kevin Ryan - Tumour Cell Death

Introduction

ryan

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

Sakamaki JI, Wilkinson S, Hahn M, Tasdemir N, O'Prey J, Clark W, Hedley A, Nixon C, Long JS, New M, Van Acker T, Tooze SA, Lowe SW, Dikic I, Ryan KM. Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function. Mol Cell 66: 517-32.e9, 2017

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

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

Current committee membership

BACR Executive Committee

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

2017

Garcia-Mariscal A, Li H, Pedersen E, Peyrollier K, Ryan KM, Stanley A, Quondamatteo F, Brakebusch C (2017) Loss of RhoA promotes skin tumor formation and invasion by upregulation of RhoB. Oncogene 2017 Oct 23. doi: 10.1038/onc.2017.333. [Epub ahead of print]

Giampazolias E, Zunino B, Dhayade S, Bock F, Cloix C, Cao K, Roca A, Lopez J, Ichim G, Proics E, Rubio-Patino C, Fort L, Yatim N, Woodham E, Orozco S, Taraborrelli L, Peltzer N, Lecis D, Machesky L, Walczak H et al. Mitochondrial permeabilization engages NF-kappaB-dependent anti-tumour activity under caspase deficiency. Nat Cell Biol 2017; 19: 1116-29

Kania E, Pajak B, O'Prey J, Sierra Gonzalez P, Litwiniuk A, Urbanska K, Ryan KM, Orzechowski A. Verapamil treatment induces cytoprotective autophagy by modulating cellular metabolism. FEBS J 2017; 284: 1370-87

Lampada A, O'Prey J, Szabadkai G, Ryan KM, Hochhauser D, Salomoni P. mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism. Cell Death Differ 2017; 24: 1045-62

Mitchell R, Hopcroft LEM, Baquero P, Allan EK, Hewit K, James D, Hamilton G, Mukhopadhyay A, O'Prey J, Hair A, Melo JV, Chan E, Ryan KM, Maguer-Satta V, Druker BJ, Clark RE, Mitra S, Herzyk P, Nicolini FE, Salomoni P et al. Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition. J Natl Cancer Inst 2017 Nov 20. doi: 10.1093/jnci/djx236. [Epub ahead of print]

O'Prey J, Sakamaki J, Baudot AD, New M, Van Acker T, Tooze SA, Long JS, Ryan KM. Application of CRISPR/Cas9 to Autophagy Research. Methods Enzymol 2017; 588: 79-108

Rosenfeldt MT, O'Prey J, Flossbach L, Nixon C, Morton JP, Sansom OJ, Ryan KM. PTEN deficiency permits the formation of pancreatic cancer in the absence of autophagy. Cell Death Differ 2017; 24: 1303-4

Sakamaki JI, Wilkinson S, Hahn M, Tasdemir N, O'Prey J, Clark W, Hedley A, Nixon C, Long JS, New M, Van Acker T, Tooze SA, Lowe SW, Dikic I, Ryan KM. Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function. Mol Cell 2017; 66: 517-32.e9

Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI, Cuervo AM, Debnath J, Deretic V, Dikic I, Eskelinen EL, Fimia GM, Fulda S, Gewirtz DA, Green DR, Hansen M et al. Molecular definitions of autophagy and related processes. EMBO J 2017; 36: 1811-36

New M, Van Acker T, Long JS, Sakamaki JI, Ryan KM, Tooze SA. Molecular Pathways Controlling Autophagy in Pancreatic Cancer. Front Oncol 2017; 7: 28

Sakamaki JI, Long JS, New M, Van Acker T, Tooze SA, Ryan KM (2017) Emerging roles of transcriptional programs in autophagy regulation. Transcription 2017 Oct 5:1-6. doi: 10.1080/21541264.2017.1372045. [Epub ahead of print]

Sakamaki JI, Ryan KM. Transcriptional regulation of autophagy and lysosomal function by bromodomain protein BRD4. Autophagy 2017; 13: 2006-7

Simon HU, Friis R, Tait SW, Ryan KM. Retrograde signaling from autophagy modulates stress responses. Sci Signal 2017; 10: pii: eaag2791.

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

Lab Members

ryan group

Post-docs

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

Principal Scientific Officer

Jim O'Prey

PhD Students

Valentin Barthet
Martina Brucoli
Christoph Noessing
Pablo Sierra-Gonzalez

Research

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Read more about the Research Groups working at the Beatson Institute.

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Seminars

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

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