Current research

Despite the overwhelming success of genetics to advance our understanding of cancer, it is still primarily a disease of signalling rather than of our genes. The reason for this apparent contradiction is the critical lack of high-throughput methods to establish the topology of biological pathways.

ER Activation
The estrogen receptor is activated by estradiol, leading to release of bound heat-shock proteins. It then dimerises and forms a complex on the DNA which activates near by genes through the mediator complex. In cancer the activation of these genes leads to tumour growth.

Andrew's research programme focuses on developing methods to meet this challenge and in applying them to the regulation of the estrogen receptor (ER) in breast cancer. In 70% of all breast cancer cases, this receptor drives the growth and proliferation of the tumour and is a key target for the drug Tamoxifen. Unfortunately for 10-40% of patients, depending on the stage of the disease at first diagnosis, the disease relapses and is often resistant to the most successful targeted therapies. As ER is known to associate with pioneer factors and numerous co-factors, including many with enzymatic activity that can modify the ER, a potential solution to resistance is to target them.

Andrew is applying the methods he developed to investigate the role of these co-factors and how they interact with the ER to produce a complete model of the signalling pathway, and to identify how the reprogramming of the pathway leads to resistance. The opportunities to undertake this kind of study are only recently possible and relies on state-of-the-art computational methods to combine proteomic and genomic data. In the long term, he aims to produce a model that could be used to predict the effects of perturbing components of the pathway with drugs and potentially lead to improved combinatorial treatment regimes.

Team

Current Members

Amy Cullen
Research Assistant
BSc (Hons), Imperial College London, UK, 2016
Funding: Cancer Research UK

Ryan Blake
Research Assistant
MSc Cancer Biology, Essex, UK, 2017
Funding: Cancer Research UK
Previously undertook MSc project in lab

Janine Lux
MPhil Project Placement, 2019
University of Essex
Funding: University of Essex

Previous Members

Simona Schindler
Visiting Student, 2019
Master of Science in Molecular Biotechnology, University of Heidelberg, Germany, 2019
Funding: ERASMUS+

Bryce Lim
Part III Student, 2019
University of Cambridge: Biochemistry

Anze Godicelj
Research Assistant, 2017
MSci BA (Hons), Univesrity of Cambridge, UK, 2017
Previously Part III Student in lab, 2016, University of Cambridge: Biochemistry awarded overall First Class.

Jade Talbot
MPhil Project Placement, 2018
University of Essex
Funding: University of Essex

Gabriella Gellen
Visiting Student, 2018
University of Debrecen, Hungary
Funding: Erasmus

Simon Wengert
Visiting Student, 2017
Molecular Biotechnologist (M. Sc.), University of Heidelberg, Germany, 2017
Funding: Cancer Research UK/Erasmus+

Jannik Lauenstein
Work Experiance Research Assistant, 2017
Apprenticeship in biology laboraty technician, Lise-Meitner-Schule, Berlin, Germany
Funding: Lise-Meitner-Schule, Berlin

George Wood
Visiting Student, 2016
Natural Sciences Tripos Undergraduate, University of Cambridge
Funding: Downing College — Bill Willetts and Mays Wild funds

Marisa Di Monaco
MPhil Project Placement, 2015
University of Essex
Funding: University of Essex

Published Research

Journal Articles

  1. Andrew N. Holding*, Federico M. Giorgi, Amanda Donnelly, Amy E. Cullen, Luke A. Selth and Florian Markowetz (2018)
    Network Dynamics of ER-α activation reveals reprogramming of GRHL2
    Genome Biology, 20, 19. [Open Access]

  2. Andrew N. Holding*, Amy E. Cullen and Florian Markowetz (2018)
    Genome-wide Estrogen Receptor-alpha activation is sustained, not cyclical
    eLife, 7, e40854. [PubMed]

  3. Euan S. Polson, Verena B. Kuchler, Christopher Abbosh, Edith M. Ross, Ryan K. Mathew, Hester A. Beard, Bárbara da Silva, Andrew N. Holding, Stephane Ballereau, Eulashini Chuntharpursat-Bon, Jennifer Williams, Hollie B. S. Griffiths, Hao Shao, Anjana Patel, Adam J. Davies, Alastair Droop, Paul Chumas, Susan C. Short, Mihaela Lorger, Jason E. Gestwicki, Lee D. Roberts, Robin. S Bon, Simon J. Allison, Shoutian Zhu, Florian Markowetz, Heiko Wurdak (2018)
    KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice
    Science translational medicine, 10, 454. [PubMed]

  4. Evangelia K. Papachristou, Kamal Kishore1, Andrew N. Holding1, … , Rasmus Siersbaek, Clive S. D’Santos and Jason S. Carroll (2018)
    A quantitative mass spectrometry-based approach to monitor the dynamics of endogenous chromatin-associated protein complexes
    Nature Communications, 9, 2311. [PubMed]

  5. Michael J. Guertin, Amy E. Cullen, Florian Markowetz and Andrew N. Holding* (2018)
    Parallel Factor ChIP Provides Essential Internal Control for Quantitative Differential ChIP-Seq
    Nucleic Acids Research. 46, 12. [PubMed]

  6. Andrew N. Holding* (2015)
    XL–MS: Protein cross-linking coupled with mass spectrometry
    Methods 89. 54-63. [PubMed]

  7. Jennifer Lee, ShuJing Ding, Thomas B. Walpole, Andrew N. Holding, Martin G. Montgomery, Ian M. Fearnley and John E. Walker (2015)
    Organisation of Subunits in the Membrane Domain of the Bovine F-ATPase Revealed by Covalent Cross-linking.
    J. Biol. Chem. 290. 13308-20. [PubMed]

  8. Andrew N Holding,* Meindert H Lamers, Elaine Stephens and J Mark Skehel (2013)
    Hekate: software suite for the mass spectrometric analysis and three-dimensional visualization of cross-linked protein samples.
    J Proteome Res. 12. 5923-33. [PubMed]

  9. Yang Liu,1 Hannah K Salter, 1 Andrew N Holding, Christopher M Johnson, Elaine Stephens, Peter J Lukavsky, John Wlashaw and Simon L Bullock (2013)
    Bicaudal-D uses a parallel, homodimeric coiled coil with heterotypic registry to coordinate recruitment of cargos to dynein.
    Genes Dev. 27. 1233-46. [PubMed]

  10. Andrew N Holding,1 Ana Toste Rego,1 Helen Kent and Meindert H Lamers (2013)
    Architecture of the Pol III—clamp—exonuclease complex reveals key roles of the exonuclease subunit in processive DNA synthesis and repair.
    EMBO J. 32. 1334-1343. [Pubmed] [F1000Prime] - recommended as being of special significance.

  11. Andrew N Holding* and Jonathan B Spencer. (2008)
    Investigation into the mechanism of phenolic couplings during the biosynthesis of glycopeptide antibiotics.
    ChemBioChem. 9. 2209-14. [Pubmed]

  12. Helen M O’Hare, Fanglu Huang, Andrew Holding, Oliver W Choroba and Jonathan B Spencer. (2006)
    Conversion of hydroxyphenylpyruvate dioxygenases into hydroxymandelate synthases by directed evolution.
    FEBS Lett. 580. 3445-50. [Pubmed]

1These authors contributed equally to this work.
* Corresponding author.

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