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1. The genomic landscape of 2,023 colorectal cancers

Author

Cornish, Alex J., Gruber, Andreas J., Kinnersley, Ben, Chubb, Daniel, Frangou, Anna, Caravagna, Giulio, Noyvert, Boris, Lakatos, Eszter, Wood, Henry M., Thorn, Steve, Culliford, Richard, Arnedo-Pac, Claudia, Househam, Jacob, Cross, William, Sud, Amit, Law, Philip, Leathlobhair, Maire Ni, Hawari, Aliah, Woolley, Connor, Sherwood, Kitty, Feeley, Nathalie, Gül, Güler, Fernandez-Tajes, Juan, Zapata, Luis, Alexandrov, Ludmil B., Murugaesu, Nirupa, Sosinsky, Alona, Mitchell, Jonathan, Lopez-Bigas, Nuria, Quirke, Philip, Church, David N., Tomlinson, Ian P. M., Sottoriva, Andrea, Graham, Trevor A., Wedge, David C., and Houlston, Richard S.

Published
2024
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2. Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer

Author

Kayhanian, Hamzeh, Cross, William, van der Horst, Suzanne E. M., Barmpoutis, Panagiotis, Lakatos, Eszter, Caravagna, Giulio, Zapata, Luis, Van Hoeck, Arne, Middelkamp, Sjors, Litchfield, Kevin, Steele, Christopher, Waddingham, William, Patel, Dominic, Milite, Salvatore, Jin, Chen, Baker, Ann-Marie, Alexander, Daniel C., Khan, Khurum, Hochhauser, Daniel, Novelli, Marco, Werner, Benjamin, van Boxtel, Ruben, Hageman, Joris H., Buissant des Amorie, Julian R., Linares, Josep, Ligtenberg, Marjolijn J. L., Nagtegaal, Iris D., Laclé, Miangela M., Moons, Leon M. G., Brosens, Lodewijk A. A., Pillay, Nischalan, Sottoriva, Andrea, Graham, Trevor A., Rodriguez-Justo, Manuel, Shiu, Kai-Keen, Snippert, Hugo J. G., and Jansen, Marnix

Published
2024
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3. Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project

Author

Ní Leathlobhair, Máire, Frangou, Anna, Kinnersley, Ben, Cornish, Alex J., Chubb, Daniel, Lakatos, Eszter, Arumugam, Prabhu, Gruber, Andreas J., Law, Philip, Tapinos, Avraam, Jakobsdottir, G. Maria, Peneva, Iliana, Sahli, Atef, Smyth, Evie M., Ball, Richard Y., Sylva, Rushan, Benes, Ksenija, Stark, Dan, Young, Robin J., Lee, Alexander T. J., Wolverson, Vincent, Houlston, Richard S., Sosinsky, Alona, Protheroe, Andrew, Murray, Matthew J., Wedge, David C., and Verrill, Clare

Published
2024
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5. The co-evolution of the genome and epigenome in colorectal cancer

Author

Heide, Timon, Househam, Jacob, Cresswell, George D., Spiteri, Inmaculada, Lynn, Claire, Mossner, Maximilian, Kimberley, Chris, Fernandez-Mateos, Javier, Chen, Bingjie, Zapata, Luis, James, Chela, Barozzi, Iros, Chkhaidze, Ketevan, Nichol, Daniel, Gunasri, Vinaya, Berner, Alison, Schmidt, Melissa, Lakatos, Eszter, Baker, Ann-Marie, Costa, Helena, Mitchinson, Miriam, Piazza, Rocco, Jansen, Marnix, Caravagna, Giulio, Ramazzotti, Daniele, Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Graham, Trevor A., and Sottoriva, Andrea

Published
2022
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6. Phenotypic plasticity and genetic control in colorectal cancer evolution

Author

Househam, Jacob, Heide, Timon, Cresswell, George D., Spiteri, Inmaculada, Kimberley, Chris, Zapata, Luis, Lynn, Claire, James, Chela, Mossner, Maximilian, Fernandez-Mateos, Javier, Vinceti, Alessandro, Baker, Ann-Marie, Gabbutt, Calum, Berner, Alison, Schmidt, Melissa, Chen, Bingjie, Lakatos, Eszter, Gunasri, Vinaya, Nichol, Daniel, Costa, Helena, Mitchinson, Miriam, Ramazzotti, Daniele, Werner, Benjamin, Iorio, Francesco, Jansen, Marnix, Caravagna, Giulio, Barnes, Chris P., Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Sottoriva, Andrea, and Graham, Trevor A.

Published
2022
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9. Immunosuppressive niche engineering at the onset of human colorectal cancer

Author

Gatenbee, Chandler D., Baker, Ann-Marie, Schenck, Ryan O., Strobl, Maximilian, West, Jeffrey, Neves, Margarida P., Hasan, Sara Yakub, Lakatos, Eszter, Martinez, Pierre, Cross, William C. H., Jansen, Marnix, Rodriguez-Justo, Manuel, Whelan, Christopher J., Sottoriva, Andrea, Leedham, Simon, Robertson-Tessi, Mark, Graham, Trevor A., and Anderson, Alexander R. A.

Published
2022
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10. Stochastic analysis and control methods for molecular cell biology

Author

Lakatos, Eszter and Stumpf, Michael P. H.

Subjects
571.6
Abstract

Stochastic fluctuations in cellular processes often have a dominant role in evoking heterogeneous behaviour in otherwise identical cells. From a modelling point of view, stochastic systems require specialised techniques to analyse and provide predictions about the underlying processes. Here we approach this problem by presenting several methods for the analysis of stochastic networks in molecular biology. First, we address the problem of obtaining simulated trajectories of such systems. This task can be computationally prohibitively expensive and a range of approximation schemes have been proposed to lighten the burden. Here, we develop a set of multivariate moment closures that allow us to describe the stochastic dynamics of nonlinear systems. We use multivariate Gaussian, lognormal, and gamma closure to capture how correlations between different molecular species, induced by the reaction dynamics, interact with stochastic effects. In addition to the approximation method we also introduce our Python-based package that provides numerous tools to help non-expert users in stochastic analysis. Next, we present an approach to quickly evaluate the levels of noise in both naturally evolved and engineered biological systems. Controlling the behaviour of cells by rationally guiding processes is an overarching aim of recent research, but stochasticity proves a formidable obstacle in obtaining reliable models and designs. Here, we compute the states reachable by a stochastic system under some biologically relevant control input in cases with uncertainty about parameter values. Our algorithm provides a set of bounds on molecular dynamics at the level of population statistics that can be used for evaluating competing models and control strategies. In the third part, we introduce a formalism to study cellular decision making influenced by noise. Understanding the heterogeneity of phenotypes within a cell population is a long-time challenge in modelling, and Waddington's notion of a developmental landscape has become a powerful conceptual framework for this problem. Here, we derive quantitative potential landscapes that allow us to explore the global dynamics of the system. Using this method we study how different sources of noise and modifications in experimental conditions can induce significant changes in the landscape and the assumed cell fates. Finally, we propose a framework for model selection taking into account the inherent stochasticity of biochemistry. One of the main objectives of mathematical biology is identifying the most appropriate models and parameter values to describe known experimental results and provide predictions. Here, we develop and apply a Bayesian computational framework to identify dominant mechanisms controlling the variation of protein abundance between cell types. Using single cell expression of p53 in two cell lines, we compare the effect of transcription and protein degradation on the steady state distribution.

Published
2017
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12. Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer

Author

CMM Groep Snippert, CMM Groep Cuppen, Cancer, Pathologie Pathologen staf, MS MDL 1, Kayhanian, Hamzeh, Cross, William, van der Horst, Suzanne E M, Barmpoutis, Panagiotis, Lakatos, Eszter, Caravagna, Giulio, Zapata, Luis, Van Hoeck, Arne, Middelkamp, Sjors, Litchfield, Kevin, Steele, Christopher, Waddingham, William, Patel, Dominic, Milite, Salvatore, Jin, Chen, Baker, Ann-Marie, Alexander, Daniel C, Khan, Khurum, Hochhauser, Daniel, Novelli, Marco, Werner, Benjamin, van Boxtel, Ruben, Hageman, Joris H, Buissant des Amorie, Julian R, Linares, Josep, Ligtenberg, Marjolijn J L, Nagtegaal, Iris D, Laclé, Miangela M, Moons, Leon M G, Brosens, Lodewijk A A, Pillay, Nischalan, Sottoriva, Andrea, Graham, Trevor A, Rodriguez-Justo, Manuel, Shiu, Kai-Keen, Snippert, Hugo J G, Jansen, Marnix, CMM Groep Snippert, CMM Groep Cuppen, Cancer, Pathologie Pathologen staf, MS MDL 1, Kayhanian, Hamzeh, Cross, William, van der Horst, Suzanne E M, Barmpoutis, Panagiotis, Lakatos, Eszter, Caravagna, Giulio, Zapata, Luis, Van Hoeck, Arne, Middelkamp, Sjors, Litchfield, Kevin, Steele, Christopher, Waddingham, William, Patel, Dominic, Milite, Salvatore, Jin, Chen, Baker, Ann-Marie, Alexander, Daniel C, Khan, Khurum, Hochhauser, Daniel, Novelli, Marco, Werner, Benjamin, van Boxtel, Ruben, Hageman, Joris H, Buissant des Amorie, Julian R, Linares, Josep, Ligtenberg, Marjolijn J L, Nagtegaal, Iris D, Laclé, Miangela M, Moons, Leon M G, Brosens, Lodewijk A A, Pillay, Nischalan, Sottoriva, Andrea, Graham, Trevor A, Rodriguez-Justo, Manuel, Shiu, Kai-Keen, Snippert, Hugo J G, and Jansen, Marnix

Published
2024

14. Epigenome and early selection determine the tumour-immune evolutionary trajectory of colorectal cancer

Author

Lakatos, Eszter, primary, Gunasri, Vinaya, additional, Zapata, Luis, additional, Househam, Jacob, additional, Heide, Timon, additional, Trahearn, Nicholas, additional, Swinyard, Ottilie, additional, Cisneros, Luis, additional, Lynn, Claire, additional, Mossner, Maximilian, additional, Kimberley, Chris, additional, Spiteri, Inmaculada, additional, Cresswell, George D., additional, Llibre-Palomar, Gerard, additional, Mitchison, Miriam, additional, Maley, Carlo C., additional, Jansen, Marnix, additional, Rodriguez-Justo, Manuel, additional, Bridgewater, John, additional, Baker, Ann-Marie, additional, Sottoriva, Andrea, additional, and Graham, Trevor A., additional

Published
2024
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16. Evolutionary dynamics of neoantigens in growing tumors

Author

Lakatos, Eszter, Williams, Marc J., Schenck, Ryan O., Cross, William C. H., Househam, Jacob, Zapata, Luis, Werner, Benjamin, Gatenbee, Chandler, Robertson-Tessi, Mark, Barnes, Chris P., Anderson, Alexander R. A., Sottoriva, Andrea, and Graham, Trevor A.

Published
2020
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17. SUZUKI-MIYAURA, SONOGASHIRA CROSS-COUPLING AND CuAAC REACTIONS SUITE FOR THE ACCESS TO A LARGE MACROCYCLE WITH m,m'-TERPHENYL MOTIF.

Author

LAKATOS, Eszter, HĂDADE, Niculina Daniela, BOGDAN, Elena, TEREC, Anamaria, and GROSU, Ion

Subjects
COUPLING reactions (Chemistry), TRIAZOLES, ESTERS
Abstract

The access to a large semirigid macrocycle exhibiting two m,m'-terphenyl units was carried out by a suite of Suzuki-Miyaura, Sonogashira crosscoupling and CuAAC ("click") reactions. The target macrocycle exhibits two triazole and two ester protected carboxyl units of great use for the development of further applications. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Evolutionary and immune microenvironment dynamics during neoadjuvant treatment of oesophagael adenocarcinoma

Author

Barroux, Melissa, primary, Househam, Jacob, additional, Lakatos, Eszter, additional, Ronel, Tahel, additional, Baker, Ann-Marie, additional, Salié, Henrike, additional, Mossner, Max, additional, Smith, Kane, additional, Kimberley, Chris, additional, Nowinski, Salpie, additional, Berner, Alison, additional, Gunasri, Vinaya, additional, Jansen, Marnix, additional, Caravagna, Giulio, additional, Steiger, Katja, additional, Slotta-Huspenina, Julia, additional, Weichert, Wilko, additional, Alberstmeier, Markus, additional, Chain, Benny, additional, Friess, Helmut, additional, Bengsch, Bertram, additional, Schmid, Roland, additional, Siveke, Jens, additional, Quante, Michael, additional, and Graham, Trevor, additional

Published
2023
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20. Abstract 4539: Tumor evolution and immune microenvironment dynamics define response to neoadjuvant treatment of esophageal adenocarcinoma

Author

Barroux, Melissa, primary, Househam, Jacob, additional, Lakatos, Eszter, additional, Ronel, Tahel, additional, Baker, Ann-Marie, additional, Salié, Henrike, additional, Mossner, Max, additional, Smith, Kane, additional, Kimberley, Chris, additional, Nowinski, Salpie, additional, Berner, Alison, additional, Gunasri, Vinaya, additional, Jansen, Marnix, additional, Caravagna, Giulio, additional, Slotta-Huspenina, Julia, additional, Weichert, Wilko, additional, Alberstmeier, Markus, additional, Chain, Benny, additional, Friess, Helmut, additional, Bengsch, Bertram, additional, Schmid, Roland M., additional, Siveke, Jens T., additional, Quante, Michael, additional, and Graham, Trevor A., additional

Published
2023
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21. Whole genome sequencing of 2,023 colorectal cancers reveals mutational landscapes, new driver genes and immune interactions

Author

Tomlinson, Ian, primary, Cornish, Alex, additional, Gruber, Andreas, additional, Houlston, Richard, additional, Sud, Amit, additional, Law, Philip, additional, Lakatos, Eszter, additional, Culliford, Richard, additional, Househam, Jacob, additional, Graham, Trevor, additional, Wood, Henry, additional, Quirke, Philip, additional, Lopez-Bigas, Nuria, additional, Arnedo-Pac, Claudia, additional, Chubb, Daniel, additional, Leathlobhair, Maire Ni, additional, Noyvert, Boris, additional, Kinnersley, Ben, additional, Cross, William, additional, Murugaesu, Nirupa, additional, Sosinsky, Alona, additional, Mitchell, Jonathan, additional, Alexandrov, Ludmil, additional, Zapata, Luis, additional, Fernandez-Tajes, Juan, additional, Thorn, Steve, additional, Sherwood, Kitty, additional, Gul, Guler, additional, Hawari, Aliah, additional, Sottoriva, Andrea, additional, Church, David, additional, Caravagna, Giulio, additional, Wedge, David, additional, and Frangou, Anna, additional

Published
2022
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23. Phenotypic plasticity and genetic control in colorectal cancer evolution

Author

Househam, J, Heide, T, Cresswell, G, Spiteri, I, Kimberley, C, Zapata, L, Lynn, C, James, C, Mossner, M, Fernandez-Mateos, J, Vinceti, A, Baker, A, Gabbutt, C, Berner, A, Schmidt, M, Chen, B, Lakatos, E, Gunasri, V, Nichol, D, Costa, H, Mitchinson, M, Ramazzotti, D, Werner, B, Iorio, F, Jansen, M, Caravagna, G, Barnes, C, Shibata, D, Bridgewater, J, Rodriguez-Justo, M, Magnani, L, Sottoriva, A, Graham, T, Househam, Jacob, Heide, Timon, Cresswell, George D., Spiteri, Inmaculada, Kimberley, Chris, Zapata, Luis, Lynn, Claire, James, Chela, Mossner, Maximilian, Fernandez-Mateos, Javier, Vinceti, Alessandro, Baker, Ann-Marie, Gabbutt, Calum, Berner, Alison, Schmidt, Melissa, Chen, Bingjie, Lakatos, Eszter, Gunasri, Vinaya, Nichol, Daniel, Costa, Helena, Mitchinson, Miriam, Ramazzotti, Daniele, Werner, Benjamin, Iorio, Francesco, Jansen, Marnix, Caravagna, Giulio, Barnes, Chris P., Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Sottoriva, Andrea, Graham, Trevor A., Househam, J, Heide, T, Cresswell, G, Spiteri, I, Kimberley, C, Zapata, L, Lynn, C, James, C, Mossner, M, Fernandez-Mateos, J, Vinceti, A, Baker, A, Gabbutt, C, Berner, A, Schmidt, M, Chen, B, Lakatos, E, Gunasri, V, Nichol, D, Costa, H, Mitchinson, M, Ramazzotti, D, Werner, B, Iorio, F, Jansen, M, Caravagna, G, Barnes, C, Shibata, D, Bridgewater, J, Rodriguez-Justo, M, Magnani, L, Sottoriva, A, Graham, T, Househam, Jacob, Heide, Timon, Cresswell, George D., Spiteri, Inmaculada, Kimberley, Chris, Zapata, Luis, Lynn, Claire, James, Chela, Mossner, Maximilian, Fernandez-Mateos, Javier, Vinceti, Alessandro, Baker, Ann-Marie, Gabbutt, Calum, Berner, Alison, Schmidt, Melissa, Chen, Bingjie, Lakatos, Eszter, Gunasri, Vinaya, Nichol, Daniel, Costa, Helena, Mitchinson, Miriam, Ramazzotti, Daniele, Werner, Benjamin, Iorio, Francesco, Jansen, Marnix, Caravagna, Giulio, Barnes, Chris P., Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Sottoriva, Andrea, and Graham, Trevor A.

Abstract

Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity1. The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather ‘plastic’. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour.

Published
2022

24. The co-evolution of the genome and epigenome in colorectal cancer

Author

Heide, T, Househam, J, Cresswell, G, Spiteri, I, Lynn, C, Mossner, M, Kimberley, C, Fernandez-Mateos, J, Chen, B, Zapata, L, James, C, Barozzi, I, Chkhaidze, K, Nichol, D, Gunasri, V, Berner, A, Schmidt, M, Lakatos, E, Baker, A, Costa, H, Mitchinson, M, Piazza, R, Jansen, M, Caravagna, G, Ramazzotti, D, Shibata, D, Bridgewater, J, Rodriguez-Justo, M, Magnani, L, Graham, T, Sottoriva, A, Heide, Timon, Househam, Jacob, Cresswell, George D., Spiteri, Inmaculada, Lynn, Claire, Mossner, Maximilian, Kimberley, Chris, Fernandez-Mateos, Javier, Chen, Bingjie, Zapata, Luis, James, Chela, Barozzi, Iros, Chkhaidze, Ketevan, Nichol, Daniel, Gunasri, Vinaya, Berner, Alison, Schmidt, Melissa, Lakatos, Eszter, Baker, Ann-Marie, Costa, Helena, Mitchinson, Miriam, Piazza, Rocco, Jansen, Marnix, Caravagna, Giulio, Ramazzotti, Daniele, Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Graham, Trevor A., Sottoriva, Andrea, Heide, T, Househam, J, Cresswell, G, Spiteri, I, Lynn, C, Mossner, M, Kimberley, C, Fernandez-Mateos, J, Chen, B, Zapata, L, James, C, Barozzi, I, Chkhaidze, K, Nichol, D, Gunasri, V, Berner, A, Schmidt, M, Lakatos, E, Baker, A, Costa, H, Mitchinson, M, Piazza, R, Jansen, M, Caravagna, G, Ramazzotti, D, Shibata, D, Bridgewater, J, Rodriguez-Justo, M, Magnani, L, Graham, T, Sottoriva, A, Heide, Timon, Househam, Jacob, Cresswell, George D., Spiteri, Inmaculada, Lynn, Claire, Mossner, Maximilian, Kimberley, Chris, Fernandez-Mateos, Javier, Chen, Bingjie, Zapata, Luis, James, Chela, Barozzi, Iros, Chkhaidze, Ketevan, Nichol, Daniel, Gunasri, Vinaya, Berner, Alison, Schmidt, Melissa, Lakatos, Eszter, Baker, Ann-Marie, Costa, Helena, Mitchinson, Miriam, Piazza, Rocco, Jansen, Marnix, Caravagna, Giulio, Ramazzotti, Daniele, Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Graham, Trevor A., and Sottoriva, Andrea

Abstract

Colorectal malignancies are a leading cause of cancer-related death1and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4–7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.

Published
2022

27. The co-evolution of the genome and epigenome in colorectal cancer

Author

Sottoriva, Andrea, primary, Heide, Timon, additional, Cresswell, George, additional, Spiteri, Inma, additional, Lynn, Claire, additional, Fernandez-Mateos, Javier, additional, Chen, Bingjie, additional, Zapata, Luis, additional, Chkhaidze, Kate, additional, Nichol, Daniel, additional, Caravagna, Giulio, additional, James, Chela, additional, Mossner, Maximilian, additional, Kimberley, Christopher, additional, Househam, Jacob, additional, Berner, Alison, additional, Schmidt, Melissa, additional, Lakatos, Eszter, additional, Baker, Ann-Marie, additional, Graham, Trevor, additional, Barozzi, Iros, additional, Costa, Helena, additional, Mitchinson, Miriam, additional, Jansen, Marnix, additional, Bridgewater, John, additional, Rodriguez-Justo, Manuel, additional, Magnani, Luca, additional, Ramazzotti, Daniele, additional, and Shibata, Darryl, additional

Published
2021
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28. Immunosuppressive niche engineering at the onset of human colorectal cancer

Author

Gatenbee, Chandler, primary, Baker, Ann-Marie, additional, Schenck, Ryan, additional, Strobl, Maximilian, additional, West, Jeffrey, additional, Neves, Margarida, additional, Hasan, Sara, additional, Lakatos, Eszter, additional, Martinez, Pierre, additional, Cross, William, additional, Jansen, Marnix, additional, Rodriguez-Justo, Manuel, additional, Whelan, Christopher, additional, Sottoriva, Andrea, additional, Leedham, Simon, additional, Robertson-Tessi, Mark, additional, Graham, Trevor, additional, and Anderson, Alexander, additional

Published
2021
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29. Phenotypic plasticity and genetic control in colorectal cancer evolution

Author

Househam, Jacob, primary, Heide, Timon, additional, Cresswell, George D, additional, Lynn, Claire, additional, Spiteri, Inmaculada, additional, Mossner, Max, additional, Kimberley, Chris, additional, Gabbutt, Calum, additional, Lakatos, Eszter, additional, Fernandez-Mateos, Javier, additional, Chen, Bingjie, additional, Zapata, Luis, additional, James, Chela, additional, Berner, Alison, additional, Schmidt, Melissa, additional, Baker, Ann-Marie, additional, Nichol, Daniel, additional, Costa, Helena, additional, Mitchinson, Miriam, additional, Jansen, Marnix, additional, Caravagna, Giulio, additional, Shibata, Darryl, additional, Bridgewater, John, additional, Rodriguez-Justo, Manuel, additional, Magnani, Luca, additional, Sottoriva, Andrea, additional, and Graham, Trevor A, additional

Published
2021
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30. Assessment of the evolutionary consequence of putative driver mutations in colorectal cancer with spatial multiomic data

Author

Heide, Timon, primary, Househam, Jacob, additional, Cresswell, George D, additional, Spiteri, Inmaculada, additional, Lynn, Claire, additional, Kimberley, Chris, additional, Mossner, Max, additional, Zapata, Luis, additional, Gabbutt, Calum, additional, Ramazzotti, Daniele, additional, Chen, Bingjie, additional, Fernandez-Mateos, Javier, additional, James, Chela, additional, Vinceti, Alessandro, additional, Berner, Alison, additional, Schmidt, Melissa, additional, Lakatos, Eszter, additional, Baker, Ann-Marie, additional, Nichol, Daniel, additional, Costa, Helena, additional, Mitchinson, Miriam, additional, Werner, Benjamin, additional, Iorio, Francesco, additional, Jansen, Marnix, additional, Barnes, Christopher, additional, Caravagna, Giulio, additional, Shibata, Darryl, additional, Bridgewater, John, additional, Rodriguez-Justo, Manuel, additional, Magnani, Luca, additional, Graham, Trevor A, additional, and Sottoriva, Andrea, additional

Published
2021
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31. The co-evolution of the genome and epigenome in colorectal cancer

Author

Heide, Timon, primary, Househam, Jacob, additional, Cresswell, George D, additional, Spiteri, Inmaculada, additional, Lynn, Claire, additional, Mossner, Max, additional, Kimberley, Chris, additional, Fernandez-Mateos, Javier, additional, Chen, Bingjie, additional, Zapata, Luis, additional, James, Chela, additional, Barozzi, Iros, additional, Chkhaidze, Ketevan, additional, Nichol, Daniel, additional, Berner, Alison, additional, Schmidt, Melissa, additional, Lakatos, Eszter, additional, Baker, Ann-Marie, additional, Costa, Helena, additional, Mitchinson, Miriam, additional, Jansen, Marnix, additional, Caravagna, Giulio, additional, Ramazzotti, Daniele, additional, Shibata, Darryl, additional, Bridgewater, John, additional, Rodriguez-Justo, Manuel, additional, Magnani, Luca, additional, Graham, Trevor A, additional, and Sottoriva, Andrea, additional

Published
2021
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32. Reconstruction of Contemporary Human Stem Cell Dynamics with Oscillatory Molecular Clocks

Author

Gabbutt, Calum, primary, Schenck, Ryan O, additional, Weisenberger, Dan, additional, Kimberley, Christopher, additional, Berner, Alison, additional, Househam, Jacob, additional, Lakatos, Eszter, additional, Robertson-Tessi, Mark, additional, Martin, Isabel, additional, Patel, Roshani, additional, Clark, Sue, additional, Latchford, Andrew, additional, Barnes, Christopher, additional, Leedham, Simon J, additional, Anderson, Alexander RA, additional, Graham, Trevor A, additional, and Shibata, Darryl, additional

Published
2021
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36. 253e IMMUNE EDITING IN THE INVASIVE MARGIN AND NODE DEPOSITS OF COLORECTAL CANCER SELECTS FOR CELLULAR NEIGHBOURHOODS ENRICHED IN PDL1+ CANCER CELLS

Author

Gunasri, Vinaya, Lakatos, Eszter, Trahearn, Nick, Cisneros, Luis, Househam, Jacob, Heide, Timon, Cresswell, George D., Spiteri, Inmaculada, Mossner, Maximilian, Kimberley, Christopher, Ortiz, Luis Zapata, James, Chela, Lynn, Claire, Berner, Alison A., Costa, Helena, Mitchison, Miriam, Jansen, Marnix, Caravagna, Giulio, Rodriguez-Justo, Manuel, Shibata, Darryl, Bridgewater, John, Baker, Ann-Marie, Sottoriva, Andrea, and Graham, Trevor A.

Published
2023
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38. Evolutionary dynamics of neoantigens in growing tumours

Author

Lakatos, Eszter, Williams, Marc J., Schenck, Ryan O., Cross, William C. H., Househam, Jacob, Werner, Benjamin, Gatenbee, Chandler, Robertson-Tessi, Mark, Barnes, Chris P., Anderson, Alexander R. A., Sottoriva, Andrea, and Graham, Trevor A.

Subjects
0303 health sciences, integumentary system, Somatic cell, Biology, Phenotype, 03 medical and health sciences, Negative selection, 0302 clinical medicine, Immune system, Antigen, 030220 oncology & carcinogenesis, Cancer research, Evolutionary dynamics, Clone (B-cell biology), Exome sequencing, 030304 developmental biology
Abstract

Cancer evolution is driven by the acquisition of somatic mutations that provide cells with a beneficial phenotype in a changing microenvironment. However, mutations that give rise to neoantigens, novel cancer–specific peptides that elicit an immune response, are likely to be disadvantageous. Here we show how the clonal structure and immunogenotype of growing tumours is shaped by negative selection in response to neoantigenic mutations. We construct a mathematical model of neoantigen evolution in a growing tumour, and verify the model using genomic sequencing data. The model predicts that, in the absence of active immune escape mechanisms, tumours either evolve clonal neoantigens (antigen– ‘hot’), or have no clonally– expanded neoantigens at all (antigen– ‘cold’), whereas antigen– ‘warm’ tumours (with high frequency subclonal neoantigens) form only following the evolution of immune evasion. Counterintuitively, strong negative selection for neoantigens during tumour formation leads to an increased number of antigen– warm or – hot tumours, as a consequence of selective pressure for immune escape. Further, we show that the clone size distribution under negative selection is effectively– neutral, and moreover, that stronger negative selection paradoxically leads to more neutral– like dynamics. Analysis of antigen clone sizes and immune escape in colorectal cancer exome sequencing data confirms these results. Overall, we provide and verify a mathematical framework to understand the evolutionary dynamics and clonality of neoantigens in human cancers that may inform patient– specific immunotherapy decision– making.

Published
2019

39. Multivariate moment closure techniques for stochastic kinetic models.

Author

Lakatos, Eszter, Ale, Angelique, Kirk, Paul D. W., and Stumpf, Michael P. H.

Subjects
*BIOCHEMISTRY, *MULTIVARIATE analysis, *STOCHASTIC models, *THERMAL expansion, *DISTRIBUTION (Probability theory)
Abstract

Stochastic effects dominate many chemical and biochemical processes. Their analysis, however, can be computationally prohibitively expensive and a range of approximation schemes have been proposed to lighten the computational burden. These, notably the increasingly popular linear noise approximation and the more general moment expansion methods, perform well for many dynamical regimes, especially linear systems. At higher levels of nonlinearity, it comes to an interplay between the nonlinearities and the stochastic dynamics, which is much harder to capture correctly by such approximations to the true stochastic processes. Moment-closure approaches promise to address this problem by capturing higher-order terms of the temporally evolving probability distribution. Here, we develop a set of multivariate moment-closures that allows us to describe the stochastic dynamics of nonlinear systems. Multivariate closure captures the way that correlations between different molecular species, induced by the reaction dynamics, interact with stochastic effects. We use multivariate Gaussian, gamma, and lognormal closure and illustrate their use in the context of two models that have proved challenging to the previous attempts at approximating stochastic dynamics: oscillations in p53 and Hes1. In addition, we consider a larger system, Erk-mediated mitogen-activated protein kinases signalling, where conventional stochastic simulation approaches incur unacceptably high computational costs. [ABSTRACT FROM AUTHOR]

Published
2015
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41. Evolutionary dynamics of neoantigens in growing tumours

Author

Lakatos, Eszter, primary, Williams, Marc J., additional, Schenck, Ryan O., additional, Cross, William C. H., additional, Househam, Jacob, additional, Werner, Benjamin, additional, Gatenbee, Chandler, additional, Robertson-Tessi, Mark, additional, Barnes, Chris P., additional, Anderson, Alexander R. A., additional, Sottoriva, Andrea, additional, and Graham, Trevor A., additional

Published
2019
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43. Supplementary Derivations and Results from Control mechanisms for stochastic biochemical systems via computation of reachable sets

Author

Lakatos, Eszter and Stumpf, Michael P. H.

Abstract

Controlling the behaviour of cells by rationally guiding molecular processes is an overarching aim of much of synthetic biology. Molecular processes, however, are notoriously noisy and frequently nonlinear. We present an approach to studying the impact of control measures on motifs of molecular interactions, that addresses the problems faced in many biological systems: stochasticity, parameter uncertainty and nonlinearity. We show that our reachability analysis formalism can describe the potential behaviour of biological (naturally evolved as well as engineered) systems, and provides a set of bounds on their dynamics at the level of population statistics: for example, we can obtain the possible ranges of means and variances of mRNA and protein expression levels, even in the presence of uncertainty about model parameters.

Published
2017
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44. Connecting the Microenvironmental Niche to Treatment Response in Ovarian Cancer

Author

Strobl, Maximilian, primary, Wicker, Matthew, additional, Adhikarla, Vikram, additional, Shockey, W. Andrew, additional, Lakatos, Eszter, additional, Pooladvand, Pantea, additional, Schenk, Ryan, additional, Saputro, Linggih, additional, Gatenbee, Chandler, additional, Koppens, Martijn, additional, García, Salvador Cruz, additional, Wenham, Robert, additional, Damaghi, Mehdi, additional, and Gallaher, Jill A., additional

Published
2018
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