Prof Daniel J Murphy - Oncogene-Induced Vulnerabilities
Introduction
Oncogenic mutations do more than simply drive unscheduled proliferation – they requisition entire suites of cellular programmes that impinge upon almost every aspect of cellular function. Our overarching hypothesis is that, as tumours evolve, some of these oncogene-induced alterations will be selectively required by cancer cells to maintain viability.
We have used a synthetic lethal approach to identify kinases required by cells that overexpress c-Myc. Intriguingly, our screen identified a number of metabolic regulators, suggesting that Myc-driven tumours may be particularly sensitive to disruption of metabolic checkpoints. Indeed we have recently demonstrated that cells overexpressing Myc are critically dependent upon AMPK and the closely related kinase ARK5 in order to maintain ATP homeostasis and thereby viability (Liu, Ulbrich et al., Nature 2012). This exciting result suggests that pharmacological suppression of Ark5/AMPK may have broad therapeutic potential against a spectrum of human cancers. Furthermore, we have developed a number of conditional transgenic mouse models of cancer that enable us to humanely track the entire course of early disease through tumour initiation and progression in situ.
The use of inducible RNAi transgenic technology will now enable us to accurately model therapeutic intervention against existing tumours in mice with a higher degree of genetic "on-target" certainty than is typically afforded by nascent pharmacological agents. The use of these models to complement cell culture based approaches is essential for a complete mechanistic understanding of the many processes involved in cancer as well as for more realistic pre-clinical evaluation of candidate therapies.
Email
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Biography
Education and qualifications
2000: PhD, University of Virginia, Supervisor Daniel Engel
1993: BSc, Biology (Magna cum Laude), University of Scranton
Appointments
2012-present: Senior Lecturer, University of Glasgow
2008-2012: Junior Group Leader, University of Würzburg, Germany
2006-2008: Research Specialist, University of California, San Francisco, USA
2001-2006: Postdoctoral Fellow with Gerard Evan, UCSF, USA
2000-2001: Postdoctoral Scientist with Mark Israel, UCSF, USA
Recent Publications
2024
Vringer E, Heilig R, Riley JS, Black A, Cloix C, Skalka G, Montes-Gómez AE, Aguado A, Lilla S, Walczak H, Gyrd-Hansen M, Murphy DJ, Huang DT, Zanivan S, Tait SW. Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response. EMBO J. 2024.
2023
Chrisochoidou Y, Roy R, Farahmand P, Gonzalez G, Doig J, Krasny L, Rimmer EF, Willis AE, MacFarlane M, Huang PH, Carragher NO, Munro AF, Murphy DJ, Veselkov K, Seckl MJ, Moffatt MF, Cookson WOC, Pardo OE. Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells. Cell Death Dis. 2023;14(11):725.
Dye I, Laing S, Garner I, Mirza HB, Iyer N, Brady N, Spiliopoulou P, Spear S, Robinson J, Fiorentino F, Fuchter MJ, Murphy DJ, McNeish IA, Brown R. cMYC-mediated immune repression is reversed by inhibition of H3K9/H3K27 methylation maintenance. bioRxiv. 2023:2023.2010.2018.562888.
Farahmand P, Gyuraszova K, Rooney C, Raffo-Iraolagoitia XL, Jayasekera G, Hedley A, Johnson E, Chernova T, Malviya G, Hall H, Monteverde T, Blyth K, Duffin R, Carlin LM, Lewis D, Le Quesne J, MacFarlane M, Murphy DJ. Asbestos accelerates disease onset in a genetic model of malignant pleural mesothelioma. Frontiers in Toxicology. 2023;5.
Laing S, Kruspig B, Shaw R, Officer-Jones L, Edwards S, McKinven D, Hsieh Y-C, Powley I, Brady N, Pennie R, Kwan R, Lima A, Myrta S, Periyasamy M, Dye IC, Nixon C, Clark G, Junttila MR, Maddalo D, Miller C, Ali S, Fuchter MJ, Nickles D, Kirschner K, Brown RB, Quesne JL, Strathdee D, Coffelt SB, Roberts E, Murphy DJ. ERBB signalling contributes to immune evasion in KRAS-driven lung adenocarcinoma. bioRxiv. 2023;Volume:2023.2007.2024.550274.
Raffo-Iraolagoitia XL, McFarlane AJ, Kruspig B, Fercoq F, Secklehner J, Donatis MD, Mackey JBG, Wiesheu R, Laing S, Hsieh Y-C, Shaw R, Corbyn R, Nixon C, Miller C, Kirschner K, Bain CC, Daniel J. Murphy, Seth B. Coffelt, Carlin LM. γδ T cells impair airway macrophage differentiation in lung adenocarcinoma. bioRxiv. 2023:2023.2009.2014.557344.
Villar VH, Allega MF, Deshmukh R, Ackermann T, Nakasone MA, Vande Voorde J, Drake TM, Oetjen J, Bloom A, Nixon C, Müller M, May S, Tan EH, Vereecke L, Jans M, Blancke G, Murphy DJ, Huang DT, Lewis DY, Bird TG, Sansom OJ, Blyth K, Sumpton D, Tardito S. Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer. Nature Chemical Biology. 2023;19:292-300.
Vincelette ND, Yu X, Kuykendall AT, Moon J, Su S, Cheng C-H, Sammut R, Razabdouski TN, Nguyen HV, Eksioglu EA, Chan O, Ali NA, Patel PC, Lee DH, Nakanishi S, Ferreira RB, Mo Q, Cory S, Lawrence HR, Zhang L, Murphy DJ, Komrokji RS, Lee D, Kaufmann SH, Cleveland JL, Yun S. A Novel Subtype of Myeloproliferative Neoplasms Driven by a MYC-Alarmin Axis. bioRxiv. 2023:2023.2009.2025.559138.
Whyte D, Skalka G, Walsh P, Wilczynska A, Paul NR, Mitchell C, Nixon C, Clarke W, Bushell M, Morton JP, Murphy DJ, Muthalagu N. NUAK1 governs centrosome replication in pancreatic cancer via MYPT1/PP1β and GSK3β-dependent regulation of PLK4. Mol Oncol. 2023; 17:1212-1227
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
Blomme A, Peter C, Mui E, Rodriguez Blanco G, An N, Mason LM, Jamieson LE, McGregor GH, Lilla S, Ntala C, Patel R, Thiry M, Kung SHY, Leclercq M, Ford CA, Rushworth LK, McGarry DJ, Mason S, Repiscak P, Nixon C, Salji MJ, Markert E, MacKay GM, Kamphorst JJ, Graham D, Faulds K, Fazli L, Gleave ME, Avezov E, Edwards J, Yin H, Sumpton D, Blyth K, Close P, Murphy DJ, Zanivan S, Leung HY. THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer. EMBO Molecular Medicine. 2022;14:e14764
Yanchus C, Drucker KL, Kollmeyer TM, Tsai R, Winick-Ng W, Liang M, Malik A, Pawling J, De Lorenzo SB, Ali A, Decker PA, Kosel ML, Panda A, Al-Zahrani KN, Jiang L, Browning JWL, Lowden C, Geuenich M, Hernandez JJ, Gosio JT, Ahmed M, Loganathan SK, Berman J, Trcka D, Michealraj KA, Fortin J, Carson B, Hollingsworth EW, Jacinto S, Mazrooei P, Zhou L, Elia A, Lupien M, He HH, Murphy DJ, Wang L, Abyzov A, Dennis JW, Maass PG, Campbell K, Wilson MD, Lachance DH, Wrensch M, Wiencke J, Mak T, Pennacchio LA, Dickel DE, Visel A, Wrana J, Taylor MD, Zadeh G, Dirks P, Eckel-Passow JE, Attisano L, Pombo A, Ida CM, Kvon EZ, Jenkins RB, Schramek D. A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation. Science. 2022;378:68-78.
2021
Grosso S, Marini A, Gyuraszova K, Voorde JV, Sfakianos A, Garland GD, Tenor AR, Mordue R, Chernova T, Morone N, Sereno M, Smith CP, Officer L, Farahmand P, Rooney C, Sumpton D, Das M, Teodósio A, Ficken C, Martin MG, Spriggs RV, Sun XM, Bushell M, Sansom OJ, Murphy D, MacFarlane M, Le Quesne JPC, Willis AE. The pathogenesis of mesothelioma is driven by a dysregulated translatome. Nat Commun. 2021;12:4920.
Mackey JBG, McFarlane AJ, Jamieson T, Jackstadt R, Raffo-Iraolagoitia XL, Secklehner J, Cortes-Lavaud X, Fercoq F, Clarke W, Hedley A, Gilroy K, Lilla S, Vuononvirta J, Graham GJ, De Filippo K, Murphy DJ, Steele CW, Norman JC, Bird TG, Mann DA, Morton JP, Zanivan S, Sansom OJ, Carlin LM. Maturation, developmental site, and pathology dictate murine neutrophil function. bioRxiv. 2021.
Yun S, Vincelette ND, Yu X, Watson GW, Fernandez MR, Yang C, Hitosugi T, Cheng CH, Freischel AR, Zhang L, Li W, Hou H, Schaub FX, Vedder AR, Cen L, McGraw KL, Moon J, Murphy DJ, Ballabio A, Kaufmann SH, Berglund AE, Cleveland JL. TFEB links MYC signaling to epigenetic control of myeloid differentiation and acute myeloid leukemia. Blood Cancer Discov. 2021;2:162-185.
2020
Muthalagu N, Monteverde T, Raffo-Iraolagoitia X, Wiesheu R, Whyte D, Hedley A, Laing S, Kruspig B, Upstill-Goddard R, Shaw R, Neidler S, Rink C, Karim SA, Gyuraszova K, Nixon C, Clark W, Biankin AV, Carlin LM, Coffelt SB, Sansom OJ, Morton JP, Murphy DJ. Repression of the Type I Interferon pathway underlies MYC & KRAS-dependent evasion of NK & B cells in Pancreatic Ductal Adenocarcinoma. Cancer discovery. 2020;
–85
2019
Bott AJ, Shen J, Tonelli C, Zhan L, Sivaram N, Jiang YP, Yu X, Bhatt V, Chiles E, Zhong H, Maimouni S, Dai W, Velasquez S, Pan JA, Muthalagu N, Morton J, Anthony TG, Feng H, Lamers WH, Murphy DJ, Guo JY, Jin J, Crawford HC, Zhang L, White E, Lin RZ, Su X, Tuveson DA, Zong WX. Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism. Cell reports. 2019;29:1287-1298.e1286
Neidler S, Kruspig B, Hewit K, Monteverde T, Gyuraszova K, Braun A, Clark W, James D, Hedley A, Nieswandt B, Shanks E, Dick C, Murphy DJ. Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma. Cancers 2019; 11: 600.
Scopelliti A, Bauer C, Yu Y, Zhang T, Kruspig B, Murphy DJ, Vidal M, Maddocks ODK, Cordero JB. A Neuronal Relay Mediates a Nutrient Responsive Gut/Fat Body Axis Regulating Energy Homeostasis in Adult Drosophila. Cell Metab 2019. 29: 269-284
2018
Kruspig B, Monteverde T, Neidler S, Hock A, Kerr E, Nixon C, Clark W, Hedley A, Laing S, Coffelt SB, Le Quesne J, Dick C, Vousden K, Martins CP, Murphy DJ. The ERBB network facilitates KRAS-driven lung tumorigenesis. Sci Transl Med 2018; 10: eaao2565
Monteverde T, Tait-Mulder J, Hedley A, Knight JR, Sansom OJ, Murphy DJ. Calcium signalling links MYC to NUAK1. Oncogene 2018; 37: 982-92
Port J, Muthalagu N, Raja M, Ceteci F, Monteverde T, Kruspig B, Hedley A, Kalna G, Lilla S, Neilson L, Brucoli M, Gyuraszova K, Tait-Mulder J, Mezna M, Svambaryte S, et al. Colorectal Tumors Require NUAK1 for Protection from Oxidative Stress. Cancer Discov 2018; 8: 632-47.
Blyth KG, Murphy DJ. Progress and challenges in Mesothelioma: From bench to bedside. Respir Med 2018; 134: 31-41.
Muthalagu N, Murphy DJ. Is oxidative stress MYC's Achilles heel? Cell Death Differ 2018; 25: 1189-90.
2017
Farrell AS, Joly MM, Allen-Petersen BL, Worth PJ, Lanciault C, Sauer D, Link J, Pelz C, Heiser LM, Morton JP, Muthalagu N, Hoffman MT, Manning SL, Pratt ED, Kendsersky ND, Egbukichi N, Amery TS, Thoma MC, Jenny ZP, Rhim AD et al. MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance. Nat Commun 2017; 8: 1728
Hock AK, Cheung EC, Humpton TJ, Monteverde T, Paulus-Hock V, Lee P, McGhee E, Scopelliti A, Murphy DJ, Strathdee D, Blyth K, Vousden KH Development of an inducible mouse model of iRFP713 to track recombinase activity and tumour development in vivo. Sci Rep. 2017; 7: 1837
Iltzsche F, Simon K, Stopp S, Pattschull G, Francke S, Wolter P, Hauser S, Murphy DJ, Garcia P, Rosenwald A, Gaubatz S. An important role for Myb-MuvB and its target gene KIF23 in a mouse model of lung adenocarcinoma. Oncogene 2017; 36: 110-21
Sarosiek KA, Fraser C, Muthalagu N, Bhola PD, Chang W, McBrayer SK, Cantlon A, Fisch S, Golomb-Mello G, Ryan JA, Deng J, Jian B, Corbett C, Goldenberg M, Madsen JR, Liao R, Walsh D, Sedivy J, Murphy DJ, Carrasco DR et al. Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics. Cancer Cell 2017; 31: 142-56
Walton JB, Farquharson M, Mason S, Port J, Kruspig B, Dowson S, Stevenson D, Murphy D, Matzuk M, Kim J, Coffelt S, Blyth K, McNeish IA. CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity. Sci Rep 2017; 7: 16827
Murphy DJ, Blyth KG. Predicting lung cancer recurrence from circulating tumour DNA. Commentary on 'Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Cell Death Differ 2017; 24: 1473-4
Port J, Murphy DJ Mesothelioma: Identical Routes to Malignancy from Asbestos and Carbon Nanotubes. Curr Biol. 2017; 27: R1173-R1176
