Daniel J Murphy - Oncogene-Induced Vulnerabilities

Introduction

murphy

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 compliment 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.


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University of Glasgow webpage

Other funding:

                   Pancreatic Cancer UK logo Worldwide Cancer Research logo

Lab Report

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 Wuerzburg, 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

2018

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, et al. MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance. Nat Commun 2017; 8(1): 1728. doi: 10.1038/s41467-017-01967-6

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(446). doi: 10.1126/scitranslmed.aao2565

Monteverde T, Tait-Mulder J, Hedley A, Knight JR, Sansom OJ, Murphy DJ. Calcium signalling links MYC to NUAK1. Oncogene 2018;37(8):982-92. doi: 10.1038/onc.2017.394

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(5):632-47. doi: 10.1158/2159-8290.CD-17-0533

Blyth KG, Murphy DJ. Progress and challenges in Mesothelioma: From bench to bedside. Respir Med 2018;134:31-41. doi: 10.1016/j.rmed.2017.11.015

Muthalagu N, Murphy DJ. Is oxidative stress MYC's Achilles heel? Cell Death Differ 2018;25(7):1189-90. doi: 10.1038/s41418-018-0117-4

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 (2017) Development of an inducible mouse model of iRFP713 to track recombinase activity and tumour development in vivo. Sci Rep 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

Monteverde T, Tait-Mulder J, Hedley A, Knight JR, Sansom OJ, Murphy DJ. Calcium signalling links MYC to NUAK1. Oncogene 2017 Nov 6. doi: 10.1038/onc.2017.394. [Epub ahead of print]

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 (2017) Mesothelioma: Identical Routes to Malignancy from Asbestos and Carbon Nanotubes. Curr Biol 27: R1173-R1176

2015

Bott AJ, I-Chen Peng I-C, Fan Y, Faubert B, Zhao L, Li J, Neidler S, Sun Y, Jaber N, Krokowski D, Lu W, Pan J-A, Powers S, Rabinowitz J, Hatzoglou M, Murphy DJ, Jones R, Wu S, Girnun G, Zong W-X. Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation. Cell Metabolism 2015. doi:10.1016/j.cmet.2015.09.025. Epub 2015 Oct 23

Ichim G, Lopez J, Ahmed SU, Muthalagu N, Giampazolias E, Delgado ME, Haller M, Riley JS, Mason SM, Athineos D, Parsons MJ, van de Kooij B, Bouchier-Hayes L, Chalmers AJ, Rooswinkel RW, Oberst A, Blyth K, Rehm M, Murphy DJ, Tait SW. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol Cell 57: 860-72, 2015

Leikam C, Hufnagel AL, Otto C, Murphy DJ, Muhling B, Kneitz S, Nanda I, Schmid M, Wagner TU, Haferkamp S, Brocker EB, Schartl M, Meierjohann S. In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells. Cell Death Dis 6: e1711, 2015

Monteverde T, Muthalagu N, Port J, Murphy DJ. Evidence of cancer-promoting roles for AMPK and related kinases. FEBS J 2015. doi: 10.1111/febs.13534. Epub 2015 Oct 1

Murphy DJ, Muthalagu N. BIM's up first. Mol Cell Oncol 2, e975083. doi: 10.4161/23723556.2014.975083

2014

Muthalagu N, Junttila MR, Wiese KE, Wolf E, Morton J, Bauer B, Evan GI, Eilers M, Murphy DJ. BIM Is the Primary Mediator of MYC-Induced Apoptosis in Multiple Solid Tissues. Cell Rep 8: 1347-53, 2014

Kamphorst JJ, Murphy DJ. The Beatson International Cancer Conference: Powering the Cancer Machine. Cancer Metab 2: 25, 2014

Lab Members

Murphy lab 036 cropped

Post-docs

Katarina Gyuraszova
Bjorn Kruspig
Nathiya Muthalagu (Worldwide Cancer Research; jointly supervised by Owen Sansom)

PhD Students

Sarah Laing
Declan Whyte (Pancreatic Cancer UK Future Leaders Academy)

Former Lab Members

Tiziana Monteverde
Jennifer Port

Research

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Seminars

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

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