Prof Kevin Ryan FRSE - Tumour Cell Death
Introduction
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.
Email
Lab Report
Key Publications
Beaumatin F, O'Prey J, Barthet VJA, Zunino B, Parvy JP, Bachmann AM, O'Prey M, Kania E, Gonzalez PS, Macintosh R, Lao LY, Nixon C, Lopez J, Long JS, Tait SWG, Ryan KM. mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux. Molecular cell. 2019; 76:163-176.e8
Gonzalez PS, O'Prey J, Cardaci S, Barthet VJA, Sakamaki JI, Beaumatin F, Roseweir A, Gay DM, Mackay G, Malviya G, Kania E, Ritchie S, Baudot AD, Zunino B, Mrowinska A, et al. Mannose impairs tumour growth and enhances chemotherapy. Nature 2018; 563:719-23
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
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; 504:296-300
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. 2013; 50: 394-406
Wilkinson S, O'Prey J, Fricker M, Ryan KM. Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity. Genes Dev. 2009; 23: 1283-8
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. 2007; 117: 1008-18
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. 2006; 126: 121-34
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 Scotland 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
Royal Society of Edinburgh Fellow Selection Panel
Scientific Advisory Board, Danish Cancer Society
International Council, NIH Center for Autophagy, Inflammation and Metabolism
North West Cancer Research Scientific Advisory Group
Honours and awards
Fellow of American Association for the Advancement of Science (AAAS), 2022
Member of Academia Europaea / Academy of Europe, 2022
Fellow of the European Academy of Cancer Sciences, 2022
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
2023
Cross J, Durgan J, McEwan DG, Tayler M, Ryan KM, Florey O.Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy. J Cell Biol. 2023;222(12).
Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023;24:560-575
Kania E, Long JS, McEwan DG, Welkenhuyzen K, La Rovere R, Luyten T, Halpin J, Lobbestael E, Baekelandt V, Bultynck G, Ryan KM, Parys JB. LRRK2 phosphorylation status and kinase activity regulate (macro)autophagy in a Rab8a/Rab10-dependent manner. Cell Death Dis. 2023;14:436.
Nössing C, Ryan KM. 50 years on and still very much alive: 'Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics'. Br J Cancer. 2023;128:426-431.
Ringborg U, von Braun J, Celis J, Baumann M, Berns A, Eggermont A, Heard E, Heitor M, Chandy M, Chen CJ, Costa A, De Lorenzo F, De Robertis EM, Dubee FC, Ernberg I, Gabriel M, Helland Å, Henrique R, Jönsson B, Kallioniemi O, Korbel J, Krause M, Lowy DR, Michielin O, Nagy P, Oberst S, Paglia V, Parker MI, Ryan K, Sawyers CL, Schüz J, Silkaitis K, Solary E, Thomas D, Turkson P, Weiderpass E, Yang H. Strategies to decrease inequalities in cancer therapeutics, care and prevention. Mol Oncol. 2023.
Ryan KM. Data sharing and management in 21st century cancer research. Mol Oncol. 2023;17:381-381
Ryan KM, Smith J, Bernards R. Molecular Oncology and the EACR: new partners in communicating and supporting cancer research. Mol Oncol. 2023;17:919-920.
Vitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, et al. Apoptotic cell death in disease-Current understanding of the NCCD 2023. Cell Death Differ. 2023;30:1097–1154
2022
Barthet VJA, Mrschtik M, Kania E, McEwan DG, Croft D, O'Prey J, Long JS, Ryan KM. DRAM-4 and DRAM-5 are compensatory regulators of autophagy and cell survival in nutrient-deprived conditions. Febs j. 2022;289: 3752-3769
Baudot AD, Wang VM, Leach JD, O'Prey J, Long JS, Paulus-Hock V, Lilla S, Thomson DM, Greenhorn J, Ghaffar F, Nixon C, Helfrich MH, Strathdee D, Pratt J, Marchesi F, Zanivan S, Ryan KM. Glycan degradation promotes macroautophagy. Proc Natl Acad Sci U S A. 2022;119(26):e2111506119.
Koessinger AL, Cloix C, Koessinger D, Heiland DH, Bock FJ, Strathdee K, Kinch K, Martínez-Escardó L, Paul NR, Nixon C, Malviya G, Jackson MR, Campbell KJ, Stevenson K, Davis S, Elmasry Y, Ahmed A, O’Prey J, Ichim G, Schnell O, Stewart W, Blyth K, Ryan KM, Chalmers AJ, Norman JC, Tait SWG. Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics. Cell Death & Differentiation. 2022; 29: 2089–2104
Long JS, Kania E, McEwan DG, Barthet VJA, Brucoli M, Ladds M, Nössing C, Ryan KM. ATG7 is a haploinsufficient repressor of tumor progression and promoter of metastasis. Proc Natl Acad Sci U S A. 2022;119:e2113465119.
Barthet VJA, Ryan KM. DRAMs and autophagy: a family affair. Autophagy Reports. 2022;1:170-174.
McEwan DG, Ryan KM. ATG2 and VPS13 proteins: molecular highways transporting lipids to drive membrane expansion and organelle communication. Febs j. 2022;289:7113-7127.
Ryan KM. In the spotlight: Julio Celis, the Founding Editor of Molecular Oncology. Mol Oncol. 2022;16(1):3-7.
Ryan KM. Navigating the current landscape of scientific publishing - the Molecular Oncology perspective. Mol Oncol. 2022;16(12):2297-9.
2021
Barthet VJA, Brucoli M, Ladds M, Nössing C, Kiourtis C, Baudot AD, O'Prey J, Zunino B, Müller M, May S, Nixon C, Long JS, Bird TG, Ryan KM. Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver. Sci Adv. 2021;7.
Latif AL, Newcombe A, Li S, Gilroy K, Robertson NA, Lei X, Stewart HJS, Cole J, Terradas MT, Rishi L, McGarry L, McKeeve C, Reid C, Clark W, Campos J, Kirschner K, Davis A, Lopez J, Sakamaki JI, Morton JP, et al. BRD4-mediated repression of p53 is a target for combination therapy in AML. Nat Commun. 2021;12:241.
Rosenfeldt MT, O'Prey J, Lindsay CR, Nixon C, Roth S, Sansom OJ, Ryan KM. Loss of autophagy affects melanoma development in a manner dependent on PTEN status. Cell Death Differ. 2021;28:1437-1439.
McEwan DG, Ryan KM. ATG2 and VPS13 proteins: molecular highways transporting lipids to drive membrane expansion and organelle communication. FEBS J. 2021
2020
Torretta S, Scagliola A, Ricci L, Mainini F, Di Marco S, Cuccovillo I, Kajaste-Rudnitski A, Sumpton D, Ryan KM, Cardaci S. D-mannose suppresses macrophage IL-1β production. Nat Comm. 2020;11(1):6343.
Gerada C, Ryan KM. Autophagy, the innate immune response and cancer. Mol Oncol. 2020; 14: 1913-1929
2019
Baquero P, Dawson A, Mukhopadhyay A, Kuntz EM, Mitchell R, Olivares O, Ianniciello A, Scott MT, Dunn K, Nicastri MC, Winkler JD, Michie AM, Ryan KM, Halsey C, Gottlieb E, Keaney EP, Murphy LO, Amaravadi RK, Holyoake TL, Helgason GV. Targeting quiescent leukemic stem cells using second generation autophagy inhibitors. Leukemia. 2019;33:981-994.
Beaumatin F, O'Prey J, Barthet VJA, Zunino B, Parvy JP, Bachmann AM, O'Prey M, Kania E, Gonzalez PS, Macintosh R, Lao LY, Nixon C, Lopez J, Long JS, Tait SWG, Ryan KM. mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux. Molecular cell. 2019;76:163-176.e8
Beauvarlet J, Bensadoun P, Darbo E, Labrunie G, Rousseau B, Richard E, Draskovic I, Londono-Vallejo A, Dupuy JW, Nath Das R, Guedin A, Robert G, Orange F, Croce S, Valesco V, et al. Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells. Nucleic acids research 2019; 47: 2739–2756
Deretic V, Prossnitz E, Burge M, Campen MJ, Cannon J, Liu KJ, Hall P, Sklar LA, Allers L, Mariscal L, Garcia SA, Baehrecke EH, Behrends C, Cecconi F, Codogno P, Chen GC, Elazar Z, Eskelinen EL, Fourie B, Gozuacik D, Hong W, Jo EK, Johansen T, Juhasz G, Kimchi A, Ktistakis N, Kroemer G, Mizushima N, Munz C, Reggiori F, Rubinsztein D, Ryan K, Schroder K, Shen HM, Simonsen A, Tooze SA, Vaccaro M, Yoshimori T, Yu L, Zhang H, Klionsky DJ. Autophagy, Inflammation, and Metabolism (AIM) Center in its second year. Autophagy. 2019; 15:1829-1833
New M, Van Acker T, Jiang M, Saunders R, Long JS, Sakamaki JI, Ryan KM, Howell M, Tooze SA. Identification and Validation of Novel Autophagy Regulators Using an Endogenous Readout siGENOME Screen. Methods in molecular biology (Clifton, NJ) 2019; 359-74.
New M, Van Acker T, Sakamaki JI, Jiang M, Saunders RE, Long J, Wang VM, Behrens A, Cerveira J, Sudhakar P, Korcsmaros T, Jefferies HBJ, Ryan KM, Howell M, Tooze SA. MDH1 and MPP7 Regulate Autophagy in Pancreatic Ductal Adenocarcinoma. Cancer research. 2019;79:1884-1898.
2018
Campbell KJ, Dhayade S, Ferrari N, Sims AH, Johnson E, Mason SM, Dickson A, Ryan KM, Kalna G, Edwards J, Tait SWG, Blyth K. MCL-1 is a prognostic indicator and drug target in breast cancer. Cell Death Dis 2018;9(2):19
Fitzwalter BE, Towers CG, Sullivan KD, Andrysik Z, Hoh M, Ludwig M, O'Prey J, Ryan KM, Espinosa JM, Morgan MJ, Thorburn A. Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover. Dev Cell 2018;44:555-565 e553
Garcia-Mariscal A, Li H, Pedersen E, Peyrollier K, Ryan KM, Stanley A, Quondamatteo F, Brakebusch C. Loss of RhoA promotes skin tumor formation and invasion by upregulation of RhoB. Oncogene 2018;37:847-860
Gonzalez PS, O'Prey J, Cardaci S, Barthet VJA, Sakamaki JI, Beaumatin F, Roseweir A, Gay DM, Mackay G, Malviya G, Kania E, Ritchie S, Baudot AD, Zunino B, Mrowinska A, et al. Mannose impairs tumour growth and enhances chemotherapy. Nature 2018; 563: 719-23.
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, et al. Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition. J Natl Cancer Inst 2018;110:467-478.
Riley JS, Quarato G, Cloix C, Lopez J, O'Prey J, Pearson M, Chapman J, Sesaki H, Carlin LM, Passos JF, Wheeler AP, Oberst A, Ryan KM, Tait SW. Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis. EMBO J 2018; 37:e99238
Barthet VJA, Ryan KM. Autophagy in Neurodegeneration: Can't Digest It, Spit It Out! Trends Cell Biol 2018;28:171-173.
Deretic V, Prossnitz E, Burge M, Campen MJ, Cannon J, Liu KJ, Sklar LA, Allers L, Garcia SA, Baehrecke EH, Behrends C, Cecconi F, Codogno P, Chen GC, Elazar Z, et al. Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence: supporting the next generation of autophagy researchers and fostering international collaborations. Autophagy 2018; 14: 925-929
Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 2018;25:486-541
Sakamaki JI, Long JS, New M, Van Acker T, Tooze SA, Ryan KM. Emerging roles of transcriptional programs in autophagy regulation. Transcription 2018;9(2):131-136.
2017
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
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, 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 p53 directly regulates the glycosidase FUCA1 to promote chemotherapy-induced cell death. Cell Cycle. 2016; 15: 2299-308
Gillespie DA, Ryan KM Autophagy is critically required for DNA repair by homologous recombination. Mol Cell Oncol. 2016; 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. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016; 12: 1-222
Mrschtik M, Ryan KM Another DRAM involved in autophagy and cell death. Autophagy 2016; 12: 603-5
Patella F, Neilson LJ, Athineos D, Erami Z, Anderson KI, Blyth K, Ryan KM, Zanivan S In-Depth Proteomics Identifies a Role for Autophagy in Controlling Reactive Oxygen Species MediatedEndothelial Permeability. Journal of proteome research 2016; 15: 2187-97
Sakamaki J, Ryan KM Autophagy Determines the Path on the TRAIL to Death. Developmental cell. 2016; 37: 291-3
