Journal ArticleDOI
Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids.
Ana C.F. Bolhaqueiro,Bas Ponsioen,Bjorn Bakker,Sjoerd J Klaasen,Emre Kucukkose,Richard H. van Jaarsveld,Judith Vivié,Ingrid Verlaan-Klink,Nizar Hami,Diana C.J. Spierings,Nobuo Sasaki,Devanjali Dutta,Sylvia F. Boj,Robert G.J. Vries,Peter M. Lansdorp,Peter M. Lansdorp,Marc van de Wetering,Alexander van Oudenaarden,Hans Clevers,Onno Kranenburg,Floris Foijer,Hugo J. Snippert,Geert J. P. L. Kops +22 more
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It is concluded that ongoing CIN is common in colorectal cancer organoids, and proposed that CIN levels and the tolerance for mitotic errors shape aneuploidy landscapes and karyotype heterogeneity.Abstract:
Chromosome segregation errors cause aneuploidy and genomic heterogeneity, which are hallmarks of cancer in humans. A persistent high frequency of these errors (chromosomal instability (CIN)) is predicted to profoundly impact tumor evolution and therapy response. It is unknown, however, how prevalent CIN is in human tumors. Using three-dimensional live-cell imaging of patient-derived tumor organoids (tumor PDOs), we show that CIN is widespread in colorectal carcinomas regardless of background genetic alterations, including microsatellite instability. Cell-fate tracking showed that, although mitotic errors are frequently followed by cell death, some tumor PDOs are largely insensitive to mitotic errors. Single-cell karyotype sequencing confirmed heterogeneity of copy number alterations in tumor PDOs and showed that monoclonal lines evolved novel karyotypes over time in vitro. We conclude that ongoing CIN is common in colorectal cancer organoids, and propose that CIN levels and the tolerance for mitotic errors shape aneuploidy landscapes and karyotype heterogeneity.read more
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Context is everything: aneuploidy in cancer
Uri Ben-David,Angelika Amon +1 more
TL;DR: The context dependency of aneuploidy in cancer is explained and its clinical potential is discussed, which may have clinical relevance as a prognostic marker and as a potential therapeutic target.
Journal ArticleDOI
Establishment of patient-derived cancer organoids for drug-screening applications
TL;DR: An overview of the protocols used by different groups to establish organoids from various epithelial tissues and cancers, plus the different protocols subsequently used to test the in vitro therapy sensitivity of these patient-derived organoids are provided.
Journal ArticleDOI
Pervasive chromosomal instability and karyotype order in tumour evolution.
Thomas B.K. Watkins,Emilia L. Lim,Emilia L. Lim,Marina Petkovic,Sergi Elizalde,Nicolai Juul Birkbak,Nicolai Juul Birkbak,Nicolai Juul Birkbak,Gareth A. Wilson,David Allan Moore,Eva Grönroos,Andrew Rowan,Sally M. Dewhurst,Jonas Demeulemeester,Jonas Demeulemeester,Stefan C. Dentro,Stefan C. Dentro,Stefan C. Dentro,Stuart Horswell,Lewis Au,Lewis Au,Kerstin Haase,Mickael Escudero,Rachel Rosenthal,Rachel Rosenthal,Maise Al Bakir,Hang Xu,Kevin Litchfield,Wei-Ting Lu,Thanos P. Mourikis,Michelle Dietzen,Lavinia Spain,Lavinia Spain,George D. Cresswell,Dhruva Biswas,Dhruva Biswas,Philippe Lamy,Iver Nordentoft,Katja Harbst,Francesc Castro-Giner,Francesc Castro-Giner,Lucy R. Yates,Lucy R. Yates,Franco Caramia,Fanny Jaulin,Cecile Vicier,Ian Tomlinson,Priscilla K. Brastianos,Priscilla K. Brastianos,Raymond J. Cho,Boris C. Bastian,Lars Dyrskjøt,Göran Jönsson,Peter Savas,Peter Savas,Sherene Loi,Sherene Loi,Peter J. Campbell,Fabrice Andre,Fabrice Andre,Nicholas M. Luscombe,Nicholas M. Luscombe,Nicholas M. Luscombe,Neeltje Steeghs,Vivianne C. G. Tjan-Heijnen,Zoltan Szallasi,Zoltan Szallasi,Samra Turajlic,Samra Turajlic,Mariam Jamal-Hanjani,Peter Van Loo,Samuel F. Bakhoum,Roland F. Schwarz,Roland F. Schwarz,Nicholas McGranahan,Charles Swanton,Charles Swanton +76 more
TL;DR: Multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types are used to show that continuous chromosomal instability results in pervasive SCNA heterogeneity.
Journal ArticleDOI
An analysis of genetic heterogeneity in untreated cancers.
Johannes G. Reiter,Marina Baretti,Jeffrey M. Gerold,Alvin Makohon-Moore,Adil Daud,Christine A. Iacobuzio-Donahue,Nilofer S. Azad,Kenneth W. Kinzler,Martin A. Nowak,Bert Vogelstein +9 more
TL;DR: The analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and it is suggested that future efforts to develop combination therapies have the potential to be curative.
Journal ArticleDOI
Genetic and non-genetic clonal diversity in cancer evolution.
TL;DR: In this paper, the authors consider the importance of both genetic and non-genetic ITH and their role in tumour evolution, and present the rationale for a broad research focus beyond the cancer genome.
References
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TL;DR: Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
Journal ArticleDOI
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.
Marco Gerlinger,Andrew Rowan,Stuart Horswell,James Larkin,David Endesfelder,Eva Grönroos,Pierre Martinez,Nicholas Matthews,Aengus Stewart,Patrick S. Tarpey,Ignacio Varela,Benjamin Phillimore,Sharmin Begum,Neil Q. McDonald,Adam Butler,David T. Jones,Keiran Raine,Calli Latimer,Claudio R. Santos,Mahrokh Nohadani,Aron Charles Eklund,Bradley Spencer-Dene,Graham Clark,Lisa Pickering,Gordon Stamp,Martin Gore,Zoltan Szallasi,Zoltan Szallasi,Julian Downward,P. Andrew Futreal,Charles Swanton +30 more
TL;DR: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development.
Journal ArticleDOI
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.
Toshiro Sato,Robert G.J. Vries,Hugo J. Snippert,Marc van de Wetering,Nick Barker,Daniel E. Stange,Johan H. van Es,Arie Abo,Pekka Kujala,Peter J. Peters,Hans Clevers +10 more
TL;DR: It is concluded that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
Journal ArticleDOI
Genetic instabilities in human cancers
TL;DR: There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels, and recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
Journal ArticleDOI
Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium.
Toshiro Sato,Daniel E. Stange,Marc Ferrante,Marc Ferrante,Robert G.J. Vries,Johan H. van Es,Stieneke van den Brink,Winan J. van Houdt,Apollo Pronk,Joost van Gorp,Peter D. Siersema,Hans Clevers +11 more
TL;DR: A technology that can be used to study infected, inflammatory, or neoplastic tissues from the human gastrointestinal tract is developed that might have applications in regenerative biology through ex vivo expansion of the intestinal epithelia.
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