Daniel J Murphy - Oncogene-Induced Vulnerabilities

University of Glasgow / Beatson Associate

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.


University of Glasgow webpage

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

2017

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 36: 110-21, 2017

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 Robinson S, Moslehi J, Letai A. Developmental regulation of mitochondrial apoptosis by c-Myc governs age- and tissue-specific sensitivity to cancer therapeutics. Cancer Cell 31: 142-56, 2017

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

2013

Bommert KS, Effenberger M, Leich E, Kuespert M, Murphy DJ, Gattenlöhner Langer C, Janz S, Moll R, Mottok A, Rosenwald A, Bargou R, Bommert K. The feed-forward loop between YB-1 and Myc is essential for Muliplte Myeloma cell survival. Leukemia 27: 441-50, 2013

2012

Liu L, Ulbrich J, Müller M, Wüstefeld T, Aeberhard L, Kress TR, Muthalagu N, Moll R, Kempa S, Zender L, Eilers M, Murphy DJ. Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature 483: 608-12, 2012

Lab Members

murphy group

Post-docs

Katarina Gyuraszova
Bjorn Kruspig
Nathiya Muthalagu (Worldwide Cancer Research)

PhD Students

Tiziana Monteverde
Jennifer Port

Research

lab image 2017 2

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

More

Seminars

lab image 2017

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

More