Mathew Garnett

Mathew Garnett
Wellcome Sanger Institute · Human Genetics Programme

About

438
Publications
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30,292
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Publications

Publications (438)
Article
Full-text available
Organoid cell culture methodologies are enabling the generation of cell models from healthy and diseased tissue. Patient-derived cancer organoids that recapitulate the genetic and histopathological diversity of patient tumours are being systematically generated, providing an opportunity to investigate new cancer biology and therapeutic approaches....
Article
Full-text available
The proteome provides unique insights into disease biology beyond the genome and transcriptome. A lack of large proteomic datasets has restricted the identification of new cancer biomarkers. Here, proteomes of 949 cancer cell lines across 28 tissue types are analyzed by mass spectrometry. Deploying a workflow to quantify 8,498 proteins, these data...
Article
Mitogen-activated protein kinase (MAPK) pathway alterations comprise some of the most frequent mutations in newly diagnosed acute myeloid leukemia (AML). Moreover, MAPK pathway alterations are also emerging as potential mechanisms of resistance to targeted therapy in AML including FLT3 inhibitors and venetoclax. In an ex vivo pharmacologic analysis...
Article
Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma (NHL) and the most common form of adult lymphoma. Despite efforts to develop new therapies, the standard of care for DLBCL remains chemotherapy based. The current standard of care is comprised of a regimen of 4 drugs (cyclophosphamide, doxorubicin, vincristine, and...
Article
Ongoing new insights in the field of cancer diagnostics, genomic profiling, and cancer behavior have raised the demand for novel, personalized cancer treatments. As the development of new cancer drugs is a challenging, costly, and time-consuming endeavor, drug repurposing is regarded as an attractive alternative to potentially accelerate this. In t...
Preprint
IFNγ signalling underpins host responses to infection, inflammation and anti-tumour immunity. Mutations in the IFNγ signalling pathway cause immunological disorders, haematological malignancies, and resistance to immune checkpoint blockade (ICB) in cancer, however the function of most clinically observed variants remain unknown. Here, we systematic...
Article
Full-text available
Combinations of anti-cancer drugs can overcome resistance and provide new treatments1,2. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combinati...
Preprint
Full-text available
The proteome provides unique insights into biology and disease beyond the genome and transcriptome. Lack of large proteomic datasets has restricted identification of new cancer biomarkers. Here, proteomes of 949 cancer cell lines across 28 tissue types were analyzed by mass spectrometry. Deploying a clinically-relevant workflow to quantify 8,498 pr...
Article
Full-text available
Background CRISPR-Cas9 genome-wide screens are being increasingly performed, allowing systematic explorations of cancer dependencies at unprecedented accuracy and scale. One of the major computational challenges when analysing data derived from such screens is to identify genes that are essential for cell survival invariantly across tissues, condit...
Preprint
Organoid cell culture methodologies are enabling the generation of cell models from healthy and diseased tissue. Patient-derived cancer organoids that recapitulate the genetic and histopathological diversity of patient tumours are being systematically generated, providing an opportunity to investigate novel cancer biology and therapeutic approaches...
Article
Full-text available
Disparities between risk, treatment outcomes and survival rates in cancer patients across the world may be attributed to socioeconomic factors. In addition, the role of ancestry is frequently discussed. In preclinical studies, high-throughput drug screens in cancer cell lines have empowered the identification of clinically relevant molecular biomar...
Conference Paper
Imipridone ONC201 is a first-in-class dopamine receptor D2 (DRD2) antagonist and mitochondrial protease ClpP agonist that is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC206, a chemical derivative of ONC201 currently in Phase I trials for central nervous system tumors, is also a DRD2 and ClpP dual targe...
Conference Paper
p>BRAF V600E mutations occur in a subset of colon cancers. These are typically resistant to chemotherapy and are associated with a poor outcome. Combination treatment with BRAF and EGFR inhibitors is superior to standard chemotherapy and has recently received FDA approval, however the early emergence of drug resistance is a significant clinical pro...
Preprint
Targeted therapeutics have advanced cancer treatment, but single agent activity remains limited by de novo and acquired resistance. Combining targeted drugs is broadly seen as a way to improve treatment outcome, motivating the ongoing search for efficacious combinations. To identify synergistic targeted therapy combinations and study the impact of...
Preprint
Full-text available
CRISPR-Cas9 recessive genome-wide pooled screens have allowed systematic explorations of weaknesses and vulnerabilities existing in cancer cells, across different tissue lineages at unprecedented accuracy and scale. The identification of novel genes essential for selective cancer cell survival is currently one of the main applications of this techn...
Article
Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer. The clinical effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of patients receiving immunotherapy have disease...
Preprint
Full-text available
Human N -myristoyltransferases (NMTs) catalyze N-terminal protein myristoylation, a modification regulating membrane trafficking and interactions of >100 proteins. NMT is a promising target in cancer, but a mechanistic rationale for targeted therapy remains poorly defined. Here, large-scale cancer cell line screens against a panel of NMT inhibitors...
Article
Full-text available
CRISPR-Cas9 viability screens are increasingly performed at a genome-wide scale across large panels of cell lines to identify new therapeutic targets for precision cancer therapy. Integrating the datasets resulting from these studies is necessary to adequately represent the heterogeneity of human cancers and to assemble a comprehensive map of cance...
Article
Full-text available
Malignant pleural mesothelioma (MPM) is an aggressive cancer most commonly caused by prior exposure to asbestos. Median survival is 12–18 months, since surgery is ineffective and chemotherapy offers minimal benefit. Preclinical models that faithfully recapitulate the genomic and histopathological features of cancer are critical for the development...
Article
Full-text available
Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identif...
Article
It is time to move beyond tumour sequencing data to identify vulnerabilities in cancers. It is time to move beyond tumour sequencing data to identify vulnerabilities in cancers.
Article
Full-text available
CRISPR guide RNA libraries have been iteratively improved to provide increasingly efficient reagents, although their large size is a barrier for many applications. We design an optimised minimal genome-wide human CRISPR-Cas9 library (MinLibCas9) by mining existing large-scale gene loss-of-function datasets, resulting in a greater than 42% reduction...
Article
Full-text available
Background Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects of its role as a biomarker in cancer is missing, as is a comprehensive analysis of the clinical significance of SLFN11 as a predictive biomarker to DDA and/or DNA damage-response inhibitor (DDR...
Article
High-throughput testing of drugs across molecular-characterised cell lines can identify candidate treatments and discover biomarkers. However, the cells’ response to a drug is typically quantified by a summary statistic from a best-fit dose-response curve, whilst neglecting the uncertainty of the curve fit and the potential variability in the raw r...
Article
Full-text available
High-throughput testing of drugs across molecular-characterised cell lines can identify candidate treatments and discover biomarkers. However, the cells' response to a drug is typically quantified by a summary statistic from a best-fit dose-response curve, whilst neglecting the uncertainty of the curve fit and the potential variability in the raw r...
Article
Full-text available
The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signalling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF mutant melanoma, with limited effect of single agent pathw...
Preprint
Drug sensitivity testing utilizing preclinical disease models such as cancer cell lines is an important and widely used tool for drug development. Importantly, when combined with molecular data such as gene copy number variation or somatic coding mutations, associations between drug sensitivity and molecular data can be used to develop markers to g...
Article
ONC201 is the first bitopic antagonist of dopamine receptor D2 (DRD2) and allosteric mitochondrial protease ClpP agonist, that is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC206, a derivative of ONC201, is also a bitopic DRD2 antagonist that exhibits enhanced non-competitive effects, nanomolar potency,...
Article
ONC206 is a DRD2 antagonist and ClpP agonist that is a chemical derivative of ONC201, which is in Phase II clinical trials for H3 K27M-mutant glioma. We have previously reported that dopamine receptor expression correlates with ONC201 and ONC206 efficacy. Here, we evaluated additional predictive biomarkers for both agents in the GDSC panel using RN...
Conference Paper
Human N-myristoyltransferase (NMT) 1 and 2 catalyze N-terminal protein myristoylation, a modification that regulates membrane trafficking and interactions of >100 proteins. NMT has been proposed as a target in cancer, but a rationale for selectivity is lacking due to the complex impact of NMT inhibition (NMTi) on multiple cellular pathways. Here, l...
Article
Full-text available
CRISPR genetic screens in cancer cell models are a powerful tool to elucidate oncogenic mechanisms and to identify promising therapeutic targets. The Project Score database (https://score.depmap.sanger.ac.uk/) uses genome-wide CRISPR–Cas9 dropout screening data in hundreds of highly annotated cancer cell models to identify genes required for cell f...
Article
Full-text available
New therapeutic targets for oral squamous cell carcinoma (OSCC) are urgently needed. We conducted genome-wide CRISPR-Cas9 screens in 21 OSCC cell lines, primarily derived from Asians, to identify genetic vulnerabilities that can be explored as therapeutic targets. We identify known and novel fitness genes and demonstrate that many previously identi...
Article
Full-text available
New therapeutic targets for oral squamous cell carcinoma (OSCC) are urgently needed. We conducted genome-wide CRISPR-Cas9 screens in 21 OSCC cell lines, primarily derived from Asians, to identify genetic vulnerabilities that can be explored as therapeutic targets. We identify known and novel fitness genes and demonstrate that many previously identi...
Article
Full-text available
New therapeutic targets for oral squamous cell carcinoma (OSCC) are urgently needed. We conducted genome-wide CRISPR-Cas9 screens in 21 OSCC cell lines, primarily derived from Asians, to identify genetic vulnerabilities that can be explored as therapeutic targets. We identify known and novel fitness genes and demonstrate that many previously identi...
Preprint
This protocol is designed to outline the process of fixing cell pellets in 1.5ml tubes. It has been developed within the Cellular Generation and Phenotyping Group at the Wellcome Sanger Institute. Process diagram:
Preprint
This protocol describes the cryopreservation and subsequent derivation of organoid models from tumour tissue. It has been developed by the organoid derivation team within the Cellular Generation and Phenotyping Group at the Wellcome Sanger Institute. We have used the process to derive organoids from colon and pancreas tumours. In our experience suc...
Article
Full-text available
Low success rates during drug development are due, in part, to the difficulty of defining drug mechanism-of-action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti-cancer drugs with genome-wide CRISPR loss-of-function screens in 484 cell lines to systematically investigate...
Preprint
This SOP defines the procedure for thawing a frozen cryovial of organoids into 1 well of a 6 well plate for further culture. It has been developed by the organoid derivation team within the Cellular Generation and Phenotyping Group at the Wellcome Sanger Institute. The team has extensive experience passaging and expanding organoid models. The metho...
Preprint
This protocol defines the procedure for cryopreservation of organoid cultures. It has been developed by the organoid derivation team within the Cellular Generation and Phenotyping Group at the Wellcome Sanger Institute. The team has extensive experience passaging and expanding organoid models. The method described has mainly been used for cancer or...
Preprint
The creation of stably Cas9 expressing cancer cell lines allows targeted and genome-wide gene modification using the CRISPR-Cas9 guide RNA system. The outcome of this process is the production of a cell line with greater than 75% Cas9 activity. Process diagram:
Article
Full-text available
Drug combinations can expand therapeutic options and address cancer’s resistance. However, the combinatorial space is enormous precluding its systematic exploration. Therefore, synergy prediction strategies are essential. We here present an approach to prioritise drug combinations in high-throughput screens and to stratify synergistic responses. At...
Conference Paper
In an era of genomics-guided precision medicine, there is an increasing need for models that reflect the hallmarks of cancer and the molecular diversity of patient tumors. New cell culturing methods are transforming our ability to derive cell models from healthy and diseased tissues, with increased success rates, and linked to patient genomic and c...
Preprint
This protocol is for the whole-genome CRISPR screening of stably expressing Cas9 cancer cell lines in triplicate using the commercially available Kusuke Yusa v1.1 whole genome gRNA library. It can be adapted for other gRNA libraries, under the assumption that there is a BFP reporter in the gRNA library. The protocol can be followed assuming the fol...
Preprint
This protocol is used to identify the optimum blasticidin concentration for the selection of Cas9 positive cancer cell lines. Process diagram:
Preprint
This protocol is used to identify the most suitable puromycin concentration for the selection of Cas9 positive cancer cell lines transduced with guideRNA library virus. Process diagram:
Preprint
This protocol is designed to outline the process of fixing cell pellets in 1.5ml tubes. It has been developed within the Cellular Generation and Phenotyping Group at the Wellcome Sanger Institute. Process diagram:
Preprint
This protocol is for the gRNA library titration of cas9 expressing cancer cell lines using the Kusuke Yusa v1.1 whole genome gRNA library. gRNA library titration is performed on all the cas9 cancer cell lines prior to gRNA library screening. The library titration allows us to determine the volume of library virus required to transduce cas9 cancer c...
Preprint
Cas9 expressing cancer cell lines need to be assessed for cas9 activity to ensure they are capable of efficiently knocking out genes. The activity is assessed by transducing the cells with a BFP-GFP vector containing an anti-GFP guide RNA. If the cas9 is active, the GFP will be knocked down so these cells will express BFP but not GFP as detected by...
Preprint
This protocol outlines routine banking of cancer cell lines and Ca9 transduced cancer lines. Process diagram:
Preprint
This SOP is for the routine maintenance and expansion of adherent cancer cell lines. It also details how cells are harvested and counted for use in downstream protocols. This protocol is also used in expasion of Cas9 transduced cell lines, prior to banking. Process diagram:
Preprint
Full-text available
CRISPR-Cas9 viability screens are being increasingly performed at a genome-wide scale across large panels of cell lines to identify new therapeutic targets for precision cancer therapy. Integrating the datasets resulting from these studies is necessary to adequately represent the heterogeneity of human cancers, and to assemble a comprehensive map o...
Preprint
Full-text available
Drug high-throughput screenings across large molecular-characterised cancer cell line panels enable the discovery of biomarkers, and thereby, cancer precision medicine. The ability to experimentally generate drug response data has accelerated. However, this data is typically quantified by a summary statistic from a best-fit dose response curve, whi...
Article
Full-text available
Selecting appropriate cancer models is a key prerequisite for maximizing translational potential and clinical relevance of in vitro oncology studies. We developed CELLector: an R package and R Shiny application allowing researchers to select the most relevant cancer cell lines in a patient-genomic-guided fashion. CELLector leverages tumor genomics...
Article
Since the approval of trastuzumab for the treatment of breast cancers more than two decades ago, many clinically effective targeted anti-cancer therapies have been developed. Here we consider the evidence that supports genomics-guided drug development and review the concept of oncogene addiction, including recent findings that inform this therapeut...
Preprint
This protocol describes the derivation of organoid models from primary tumour tissue. It has been developed by the organoid derivation team within the Cellular Generation and Phenotyping Group at the Wellcome Sanger Institute. We have used the process to derive organoids from colon, pancreas and oesophageal tumours. The team has extensive experienc...
Preprint
This protocol describes the passaging of organoid cultures. It has been developed by the organoid derivation team within the Cellular Generation and Phenotyping Group at the Wellcome Sanger Institute. The team has extensive experience passaging and expanding organoid models. The method described has mainly been used for the passaging cancer organoi...
Article
Full-text available
Mechanistic modeling of signaling pathways mediating patient-specific response to therapy can help to unveil resistance mechanisms and improve therapeutic strategies. Yet, creating such models for patients, in particular for solid malignancies, is challenging. A major hurdle to build these models is the limited material available that precludes the...
Preprint
Full-text available
Low success rates during drug development are due in part to the difficulty of defining drug mechanism-of-action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti-cancer drugs and genome-wide CRISPR loss-of-function screens in 484 cell lines to systematically investigate in...
Article
Full-text available
Genome-scale CRISPR-Cas9 viability screens performed in cancer cell lines provide a systematic approach to identify cancer dependencies and new therapeutic targets. As multiple large-scale screens become available, a formal assessment of the reproducibility of these experiments becomes necessary. We analyze data from recently published pan-cancer C...
Article
We report the derivation of 30 patient-derived organoid lines (PDOs) from tumors arising in the pancreas and distal bile duct. PDOs recapitulate tumor histology and contain genetic alterations typical of pancreatic cancer. In vitro testing of a panel of 76 therapeutic agents revealed sensitivities currently not exploited in the clinic, and undersco...
Article
Full-text available
Imipridones constitute a novel class of antitumor agents. Here, we report that a second-generation imipridone, ONC212, possesses highly increased antitumor activity compared to the first-generation compound ONC201. In vitro studies using human acute myeloid leukemia (AML) cell lines, primary AML, and normal bone marrow (BM) samples demonstrate that...
Conference Paper
cancer cell cultures are facile experimental models used widely for research and drug development. Many cancer cell lines are available and efforts are ongoing to derive new models representing the histopathological and molecular diversity of tumours. Cell models have been generated by multiple laboratories over decades and consequently their annot...
Conference Paper
The next-generation sequencing of tumors is providing an increasingly detailed description of the molecular alterations that occur across the diversity of human cancers. An important and challenging next step is to convert this wealth of information into new therapeutic hypotheses to guide patient care. My laboratory integrates cancer genomics, exp...
Preprint
Full-text available
CRISPR guide-RNA libraries have been iteratively optimised to provide increasingly efficient reagents although their large size is a barrier for some applications. We designed a minimal genome-wide human CRISPR-Cas9 library (MinLibCas9), optimised by mining existing large-scale gene loss-of-function datasets, resulting in a greater than 46% reducti...