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9 results on '"Young, Matthew D."'

1. Intra-tumour diversification in colorectal cancer at the single-cell level

Author

Roerink, Sophie F., Sasaki, Nobuo, Lee-Six, Henry, Young, Matthew D., Alexandrov, Ludmil B., Behjati, Sam, and Mitchell, Thomas J.

Subjects
Colorectal cancer -- Physiological aspects -- Development and progression, Methylation, Tumors, Cancer cells, Epigenetic inheritance, Antineoplastic agents, Phylogeny, DNA, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.Organoids derived from individual cells from colorectal cancers and adjacent normal tissue are used to investigate intra-tumour diversification at the genomic, epigenetic and functional levels., Author(s): Sophie F. Roerink [sup.1] , Nobuo Sasaki [sup.2] [sup.11] , Henry Lee-Six [sup.1] , Matthew D. Young [sup.1] , Ludmil B. Alexandrov [sup.3] [sup.4] [sup.5] , Sam Behjati [sup.1] [...]

Published
2018
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2. Single cell derived mRNA signals across human kidney tumors

Author

Groep Holstege, Pathologie Pathologen staf, Speerpunt, Zorg en O&O, Child Health, CMM Groep Burgering, Cancer, Young, Matthew D., Mitchell, Thomas J., Custers, Lars, Margaritis, Thanasis, Morales-Rodriguez, Francisco, Kwakwa, Kwasi, Khabirova, Eleonora, Kildisiute, Gerda, Oliver, Thomas R.W., de Krijger, Ronald R., van den Heuvel-Eibrink, Marry M., Comitani, Federico, Piapi, Alice, Bugallo-Blanco, Eva, Thevanesan, Christine, Burke, Christina, Prigmore, Elena, Ambridge, Kirsty, Roberts, Kenny, Braga, Felipe A.Vieira, Coorens, Tim H.H., Del Valle, Ignacio, Wilbrey-Clark, Anna, Mamanova, Lira, Stewart, Grant D., Gnanapragasam, Vincent J., Rampling, Dyanne, Sebire, Neil, Coleman, Nicholas, Hook, Liz, Warren, Anne, Haniffa, Muzlifah, Kool, Marcel, Pfister, Stefan M., Achermann, John C., He, Xiaoling, Barker, Roger A., Shlien, Adam, Bayraktar, Omer A., Teichmann, Sarah A., Holstege, Frank C., Meyer, Kerstin B., Drost, Jarno, Straathof, Karin, Behjati, Sam, Groep Holstege, Pathologie Pathologen staf, Speerpunt, Zorg en O&O, Child Health, CMM Groep Burgering, Cancer, Young, Matthew D., Mitchell, Thomas J., Custers, Lars, Margaritis, Thanasis, Morales-Rodriguez, Francisco, Kwakwa, Kwasi, Khabirova, Eleonora, Kildisiute, Gerda, Oliver, Thomas R.W., de Krijger, Ronald R., van den Heuvel-Eibrink, Marry M., Comitani, Federico, Piapi, Alice, Bugallo-Blanco, Eva, Thevanesan, Christine, Burke, Christina, Prigmore, Elena, Ambridge, Kirsty, Roberts, Kenny, Braga, Felipe A.Vieira, Coorens, Tim H.H., Del Valle, Ignacio, Wilbrey-Clark, Anna, Mamanova, Lira, Stewart, Grant D., Gnanapragasam, Vincent J., Rampling, Dyanne, Sebire, Neil, Coleman, Nicholas, Hook, Liz, Warren, Anne, Haniffa, Muzlifah, Kool, Marcel, Pfister, Stefan M., Achermann, John C., He, Xiaoling, Barker, Roger A., Shlien, Adam, Bayraktar, Omer A., Teichmann, Sarah A., Holstege, Frank C., Meyer, Kerstin B., Drost, Jarno, Straathof, Karin, and Behjati, Sam

Published
2021

3. Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours

Author

PMC Medisch specialisten, Cancer, Neurochirurgen, Speerpunt, Zorg en O&O, Child Health, Pathologie Pathologen staf, Custers, Lars, Khabirova, Eleonora, Coorens, Tim H.H., Oliver, Thomas R.W., Calandrini, Camilla, Young, Matthew D., Vieira Braga, Felipe A., Ellis, Peter, Mamanova, Lira, Segers, Heidi, Maat, Arie, Kool, Marcel, Hoving, Eelco W., van den Heuvel-Eibrink, Marry M., Nicholson, James, Straathof, Karin, Hook, Liz, de Krijger, Ronald R., Trayers, Claire, Allinson, Kieren, Behjati, Sam, Drost, Jarno, PMC Medisch specialisten, Cancer, Neurochirurgen, Speerpunt, Zorg en O&O, Child Health, Pathologie Pathologen staf, Custers, Lars, Khabirova, Eleonora, Coorens, Tim H.H., Oliver, Thomas R.W., Calandrini, Camilla, Young, Matthew D., Vieira Braga, Felipe A., Ellis, Peter, Mamanova, Lira, Segers, Heidi, Maat, Arie, Kool, Marcel, Hoving, Eelco W., van den Heuvel-Eibrink, Marry M., Nicholson, James, Straathof, Karin, Hook, Liz, de Krijger, Ronald R., Trayers, Claire, Allinson, Kieren, Behjati, Sam, and Drost, Jarno

Published
2021

4. An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures

Author

Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Zooloxía, Xenética e Antropoloxía Física, Collord, Grace, Tarpey, Patrick, Kurbatova, Natalja, Martincorena, Inigo, Morán, Sebastián, Castro, Manuel, Nagy, Tibor, Bignell, Graham, Maura, Francesco, Young, Matthew D., Berna, Jorge, Castro Tubío, José Manuel, McMurran, Chris E., Young, Adam M.H., Sanders, Mathijs, Noorani, Imran, Price, Stephen J., Watts, Colin, Leipnitz, Elke, Kirsch, Matthias, Schackert, Gabriele, Pearson, Danita, Devadass, Abel, Ram, Zvi, Collins, V. Peter, Allinson, Kieren, Jenkinson, Michael D., Zakaria, Rasheed, Syed, Khaja, Hanemann, C. Oliver, Dunn, Jemma, McDermott, Michael W., Kirollos, Ramez W., Vassiliou, George S., Esteller, Manel, Behjati, Sam, Brazma, Alvis, Santarius, Thomas, McDermott, Ultan, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Zooloxía, Xenética e Antropoloxía Física, Collord, Grace, Tarpey, Patrick, Kurbatova, Natalja, Martincorena, Inigo, Morán, Sebastián, Castro, Manuel, Nagy, Tibor, Bignell, Graham, Maura, Francesco, Young, Matthew D., Berna, Jorge, Castro Tubío, José Manuel, McMurran, Chris E., Young, Adam M.H., Sanders, Mathijs, Noorani, Imran, Price, Stephen J., Watts, Colin, Leipnitz, Elke, Kirsch, Matthias, Schackert, Gabriele, Pearson, Danita, Devadass, Abel, Ram, Zvi, Collins, V. Peter, Allinson, Kieren, Jenkinson, Michael D., Zakaria, Rasheed, Syed, Khaja, Hanemann, C. Oliver, Dunn, Jemma, McDermott, Michael W., Kirollos, Ramez W., Vassiliou, George S., Esteller, Manel, Behjati, Sam, Brazma, Alvis, Santarius, Thomas, and McDermott, Ultan

Abstract

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance

Published
2018

5. Intra-tumour diversification in colorectal cancer at the single-cell level

Author

CMM Cell Screening Center, Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Regenerative Medicine and Stem Cells, Child Health, Cancer, Roerink, Sophie F., Sasaki, Nobuo, Lee-Six, Henry, Young, Matthew D., Alexandrov, Ludmil B., Behjati, Sam, Mitchell, Thomas J., Grossmann, Sebastian, Lightfoot, Howard, Egan, David A., Pronk, Apollo, Smakman, Niels, Van Gorp, Joost, Anderson, Elizabeth, Gamble, Stephen J., Alder, Chris, Van De Wetering, Marc, Campbell, Peter J., Stratton, Michael R., Clevers, Hans, CMM Cell Screening Center, Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Regenerative Medicine and Stem Cells, Child Health, Cancer, Roerink, Sophie F., Sasaki, Nobuo, Lee-Six, Henry, Young, Matthew D., Alexandrov, Ludmil B., Behjati, Sam, Mitchell, Thomas J., Grossmann, Sebastian, Lightfoot, Howard, Egan, David A., Pronk, Apollo, Smakman, Niels, Van Gorp, Joost, Anderson, Elizabeth, Gamble, Stephen J., Alder, Chris, Van De Wetering, Marc, Campbell, Peter J., Stratton, Michael R., and Clevers, Hans

Published
2018

7. Inherent mosaicism and extensive mutation of human placentas.

Author

Coorens THH, Oliver TRW, Sanghvi R, Sovio U, Cook E, Vento-Tormo R, Haniffa M, Young MD, Rahbari R, Sebire N, Campbell PJ, Charnock-Jones DS, Smith GCS, and Behjati S

Subjects
Biopsy, Blastocyst Inner Cell Mass cytology, Female, Genome, Human genetics, Humans, Mesoderm cytology, Mutation Rate, Placenta cytology, Pregnancy, Trisomy genetics, Trophoblasts cytology, Trophoblasts metabolism, Zygote cytology, Mosaicism, Mutagenesis, Mutation, Placenta metabolism
Abstract

Placentas can exhibit chromosomal aberrations that are absent from the fetus 1 . The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. Here we investigated the phylogeny of human placental cells as reconstructed from somatic mutations, using whole-genome sequencing of 86 bulk placental samples (with a median weight of 28 mg) and of 106 microdissections of placental tissue. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Notably, there were some cases with full segregation-within a few cell divisions of the zygote-of placental lineages and lineages derived from the inner cell mass. Such early embryonic bottlenecks may enable the normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development.

Published
2021
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8. Decoding human fetal liver haematopoiesis.

Author

Popescu DM, Botting RA, Stephenson E, Green K, Webb S, Jardine L, Calderbank EF, Polanski K, Goh I, Efremova M, Acres M, Maunder D, Vegh P, Gitton Y, Park JE, Vento-Tormo R, Miao Z, Dixon D, Rowell R, McDonald D, Fletcher J, Poyner E, Reynolds G, Mather M, Moldovan C, Mamanova L, Greig F, Young MD, Meyer KB, Lisgo S, Bacardit J, Fuller A, Millar B, Innes B, Lindsay S, Stubbington MJT, Kowalczyk MS, Li B, Ashenberg O, Tabaka M, Dionne D, Tickle TL, Slyper M, Rozenblatt-Rosen O, Filby A, Carey P, Villani AC, Roy A, Regev A, Chédotal A, Roberts I, Göttgens B, Behjati S, Laurenti E, Teichmann SA, and Haniffa M

Subjects
Blood Cells cytology, Cellular Microenvironment, Female, Fetus metabolism, Flow Cytometry, Gene Expression Profiling, Humans, Liver metabolism, Lymphoid Tissue cytology, Single-Cell Analysis, Stem Cells metabolism, Fetus cytology, Hematopoiesis, Liver cytology, Liver embryology
Abstract

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.

Published
2019
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9. An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures.

Author

Collord G, Tarpey P, Kurbatova N, Martincorena I, Moran S, Castro M, Nagy T, Bignell G, Maura F, Young MD, Berna J, Tubio JMC, McMurran CE, Young AMH, Sanders M, Noorani I, Price SJ, Watts C, Leipnitz E, Kirsch M, Schackert G, Pearson D, Devadass A, Ram Z, Collins VP, Allinson K, Jenkinson MD, Zakaria R, Syed K, Hanemann CO, Dunn J, McDermott MW, Kirollos RW, Vassiliou GS, Esteller M, Behjati S, Brazma A, Santarius T, and McDermott U

Subjects
Aged, DNA Methylation genetics, Disease Progression, Female, Gene Expression Profiling, Genomics methods, Humans, Male, Meningeal Neoplasms mortality, Meningeal Neoplasms pathology, Meningeal Neoplasms surgery, Meningioma mortality, Meningioma pathology, Meningioma surgery, Middle Aged, Neoplasm Grading, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local pathology, Prognosis, Survival Analysis, Whole Genome Sequencing, Gene Expression Regulation, Neoplastic, Meningeal Neoplasms genetics, Meningioma genetics, Neoplasm Recurrence, Local genetics, Transcriptome genetics
Abstract

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance.

Published
2018
Full Text
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