Dr Mathew Garnett, PhD | Group Leader

Garnett, Mathew

Mathew's research team investigate how genetic alterations contribute to cancer and impact on patient responses to anti-cancer medicines.

This provides fundamental insights into cancer biology with direct links to the development of new cancer therapies.

Mathew's expertise is in molecular cell biology, high-throughput chemical and genetic screens, cancer genomics and anti-cancer therapeutics.

Mathew joined the Sanger Institute in 2009 as a Senior Staff Scientist and was appointed a member of Faculty in 2014. Here he developed high-throughput drug sensitivity screens in cancer cells to identify molecular features of cells that are predictive of drug response to help inform the development of new anti-cancer therapies. This work is on-going but has already led to the identification of new putative molecular biomarkers with potential to improve cancer treatments; several publications; the launch of a therapeutics website as a resource for the cancer research community; and contributed to the initiation of clinical trials.

In addition, he is performing CRISPR-Cas9 genetic screens in cancer cells to identify new drug targets and he is passionate about developing new cancer models such as cancer organoids which better capture the heterogeneity and hallmarks of patient tumours.

Mathew is a member of the scientific leadership team for the Centre for Therapeutic Target Validation (CTTV), which aims to use genome-scale experiments and analysis to evaluate new therapeutic targets, as well as a member of the Cancer Research UK drug discovery small molecule expert review panel.

Prior to joining the Sanger Institute, Mathew performed his postdoctoral work in the laboratory of Professor Ashok Venkitaraman (Cambridge University, UK) with a fellowship from the Canadian Institute of Health Research. Here he developed small interfering RNA screens using high-content microscopy to understand how cells respond to anti-mitotic cancer drugs. Mathew identified the ubiquitin-conjugating enzyme UBE2S as a novel regulator of the Anaphase Promoting Complex (APC). UBE2S is necessary for ubiquitination of APC substrates, allowing progression through mitosis following mitotic checkpoint inactivation. This work identified a new component of the mitotic checkpoint machinery, provided fresh insights into the regulation of APC activity and contributed towards our understanding of the mechanisms that control the cellular response to mitotic checkpoint arrest.

Mathew completed his PhD in 2005 in the laboratory of Richard Marais at The Institute of Cancer Research (London, UK), where he was involved in the discovery and characterisation of BRAF as a human cancer gene. His PhD work elucidated how cancer-associated mutations perturb RAF activity and demonstrated that RAF-family kinases oligomerise in cells to activate the ERK-pathway, identifying a new paradigm in the regulation of RAF signalling. This was subsequently shown to have important implications for clinical deployment of therapies targeting RAF proteins in cancer.

Mathew graduated in 1999 with a BSc. in Biochemistry (Hons.) from the University of British Columbia, Canada.

Throughout Mathew's scientific career he has strived to understand how genetic changes in cancers can be exploited to develop new cancer therapies. Several of his publications are highly cited and his research has directly contributed to the development and testing of new cancer therapies. Mathew fosters a multi-disciplinary and collaborative approach in his research team to enable the best possible research.

Publications

  • Prospective derivation of a living organoid biobank of colorectal cancer patients.

    van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F et al.

    Cell 2015;161;4;933-45

  • Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells.

    Yang W, Soares J, Greninger P, Edelman EJ, Lightfoot H et al.

    Nucleic acids research 2013;41;Database issue;D955-61

  • Systematic identification of genomic markers of drug sensitivity in cancer cells.

    Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A et al.

    Nature 2012;483;7391;570-5

  • UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit.

    Garnett MJ, Mansfeld J, Godwin C, Matsusaka T, Wu J et al.

    Nature cell biology 2009;11;11;1363-9

  • Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization.

    Garnett MJ, Rana S, Paterson H, Barford D and Marais R

    Molecular cell 2005;20;6;963-9

  • Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.

    Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D et al.

    Cell 2004;116;6;855-67

  • A Road Map for Precision Cancer Medicine Using Personalized Models.

    Picco G and Garnett MJ

    Cancer discovery 2017;7;5;456-458

  • Drug resistance mechanisms in colorectal cancer dissected with cell type-specific dynamic logic models.

    Eduati F, Doldàn-Martelli V, Klinger B, Cokelaer T, Sieber A et al.

    Cancer research 2017

  • Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations.

    Brammeld JS, Petljak M, Martincorena I, Williams SP, Alonso LG et al.

    Genome research 2017;27;4;613-625

  • Revisiting olfactory receptors as putative drivers of cancer.

    Ranzani M, Iyer V, Ibarra-Soria X, Del Castillo Velasco-Herrera M, Garnett M et al.

    Wellcome open research 2017;2;9

  • Logic models to predict continuous outputs based on binary inputs with an application to personalized cancer therapy.

    Knijnenburg TA, Klau GW, Iorio F, Garnett MJ, McDermott U et al.

    Scientific reports 2016;6;36812

  • A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds.

    Bruna A, Rueda OM, Greenwood W, Batra AS, Callari M et al.

    Cell 2016;167;1;260-274.e22

  • Drug Sensitivity Assays of Human Cancer Organoid Cultures.

    Francies HE, Barthorpe A, McLaren-Douglas A, Barendt WJ and Garnett MJ

    Methods in molecular biology (Clifton, N.J.) 2016

  • A Landscape of Pharmacogenomic Interactions in Cancer.

    Iorio F, Knijnenburg TA, Vis DJ, Bignell GR, Menden MP et al.

    Cell 2016;166;3;740-54

  • Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC-dependence in intrahepatic cholangiocarcinoma.

    Saha SK, Gordan JD, Kleinstiver BP, Vu P, Najem MS et al.

    Cancer discovery 2016

  • Multilevel models improve precision and speed of IC50 estimates.

    Vis DJ, Bombardelli L, Lightfoot H, Iorio F, Garnett MJ and Wessels LF

    Pharmacogenomics 2016;17;7;691-700

  • Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination.

    Ham J, Costa C, Sano R, Lochmann TL, Sennott EM et al.

    Cancer cell 2016;29;2;159-72

  • Pharmacogenomic agreement between two cancer cell line data sets.

    Cancer Cell Line Encyclopedia Consortium and Genomics of Drug Sensitivity in Cancer Consortium

    Nature 2015;528;7580;84-7

  • LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation.

    Mardilovich K, Baugh M, Crighton D, Kowalczyk D, Gabrielsen M et al.

    Oncotarget 2015;6;36;38469-86

  • Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells.

    Hearn JM, Romero-Canelón I, Munro AF, Fu Y, Pizarro AM et al.

    Proceedings of the National Academy of Sciences of the United States of America 2015;112;29;E3800-5

  • Prospective derivation of a living organoid biobank of colorectal cancer patients.

    van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F et al.

    Cell 2015;161;4;933-45

  • BRAF/NRAS wild-type melanoma, NF1 status and sensitivity to trametinib.

    Ranzani M, Alifrangis C, Perna D, Dutton-Regester K, Pritchard A et al.

    Pigment cell & melanoma research 2015;28;1;117-9

  • Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma.

    Gill SJ, Travers J, Pshenichnaya I, Kogera FA, Barthorpe S et al.

    PloS one 2015;10;10;e0140988

  • What role could organoids play in the personalization of cancer treatment?

    Francies HE and Garnett MJ

    Pharmacogenomics 2015;16;14;1523-6

  • Fast randomization of large genomic datasets while preserving alteration counts.

    Gobbi A, Iorio F, Dawson KJ, Wedge DC, Tamborero D et al.

    Bioinformatics (Oxford, England) 2014;30;17;i617-23

  • The evolving role of cancer cell line-based screens to define the impact of cancer genomes on drug response.

    Garnett MJ and McDermott U

    Current opinion in genetics & development 2014;24;114-9

  • Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma.

    He L, Torres-Lockhart K, Forster N, Ramakrishnan S, Greninger P et al.

    Cancer discovery 2013;3;3;324-37

  • Targeting MYCN in neuroblastoma by BET bromodomain inhibition.

    Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J et al.

    Cancer discovery 2013;3;3;308-23

  • VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer.

    Hart S, Novotny-Diermayr V, Goh KC, Williams M, Tan YC et al.

    Molecular cancer therapeutics 2013;12;2;151-61

  • Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells.

    Yang W, Soares J, Greninger P, Edelman EJ, Lightfoot H et al.

    Nucleic acids research 2013;41;Database issue;D955-61

  • MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling.

    Huang S, Hölzel M, Knijnenburg T, Schlicker A, Roepman P et al.

    Cell 2012;151;5;937-50

  • Systematic identification of genomic markers of drug sensitivity in cancer cells.

    Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A et al.

    Nature 2012;483;7391;570-5

  • Exploiting genetic complexity in cancer to improve therapeutic strategies.

    Garnett MJ and McDermott U

    Drug discovery today 2012;17;5-6;188-93

  • A mitotic function for the high-mobility group protein HMG20b regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor.

    Lee M, Daniels MJ, Garnett MJ and Venkitaraman AR

    Oncogene 2011;30;30;3360-9

  • UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit.

    Garnett MJ, Mansfeld J, Godwin C, Matsusaka T, Wu J et al.

    Nature cell biology 2009;11;11;1363-9

  • Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization.

    Garnett MJ, Rana S, Paterson H, Barford D and Marais R

    Molecular cell 2005;20;6;963-9

  • Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF.

    Emuss V, Garnett M, Mason C and Marais R

    Cancer research 2005;65;21;9719-26

  • Guilty as charged: B-RAF is a human oncogene.

    Garnett MJ and Marais R

    Cancer cell 2004;6;4;313-9

  • Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.

    Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D et al.

    Cell 2004;116;6;855-67

  • ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation.

    Morrison KB, Tognon CE, Garnett MJ, Deal C and Sorensen PH

    Oncogene 2002;21;37;5684-95

  • Mutations of the BRAF gene in human cancer.

    Davies H, Bignell GR, Cox C, Stephens P, Edkins S et al.

    Nature 2002;417;6892;949-54

  • The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation.

    Tognon C, Garnett M, Kenward E, Kay R, Morrison K and Sorensen PH

    Cancer research 2001;61;24;8909-16

  • ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma.

    Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy PE and Sorensen PH

    Cancer research 1998;58;22;5046-8

Career/Research Highlights