Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids

Bolhaqueiro, Ana C.F.; Ponsioen, Bas; Bakker, Björn; Klaasen, Sjoerd J.; Küçükköse, Emre; Jaarsveld, Richard H. van; Vivié, Judith; Verlaan-Klink, Ingrid; Hami, Nizar; Spierings, Diana C.J.; Sasaki, Nobuo; Dutta, Devanjali; Boj, Sylvia F.; Vries, Robert G.J.; Lansdorp, Peter M; Wetering, Marc van de; Oudenaarden, Alexander van; Clevers, Hans; Kranenburg, Onno; Foijer, Floris; Snippert, Hugo J.G.; Kops, Geert J.P.L.

doi:10.1038/s41588-019-0399-6

Cited by 185 publications

(170 citation statements)

References 69 publications

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“…1e). Moreover, single cell whole genome karyotype sequencing (scKaryo-seq 44 ) showed that both aneuploidy and karyotype heterogeneity were enhanced in vivo in the small intestine one week after induction of moderate, high, and very high CIN ( Fig. 1f, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Degree and site of chromosomal instability define its oncogenic potential

et al. 2020

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Most human cancers are aneuploid, due to a chromosomal instability (CIN) phenotype. Despite being hallmarks of cancer, however, the roles of CIN and aneuploidy in tumor formation have not unequivocally emerged from animal studies and are thus still unclear. Using a conditional mouse model for diverse degrees of CIN, we find that a particular range is sufficient to drive very early onset spontaneous adenoma formation in the intestine. In mice predisposed to intestinal cancer (Apc Min/+ ), moderate CIN causes a remarkable increase in adenoma burden in the entire intestinal tract and especially in the distal colon, which resembles human disease. Strikingly, a higher level of CIN promotes adenoma formation in the distal colon even more than moderate CIN does, but has no effect in the small intestine. Our results thus show that CIN can be potently oncogenic, but that certain levels of CIN can have contrasting effects in distinct tissues.

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Section: Resultsmentioning

confidence: 99%

Degree and site of chromosomal instability define its oncogenic potential

et al. 2020

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“…Single‐cell karyotype sequencing (scKaryo‐seq) was performed as described previously with some modifications (Bolhaqueiro et al , ). Briefly, nuclei were isolated from cells using a nuclear staining buffer (Bakker et al , ).…”

Section: Methodsmentioning

confidence: 99%

Human chromosome‐specific aneuploidy is influenced by DNA ‐dependent centromeric features

et al. 2019

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Intrinsic genomic features of individual chromosomes can contribute to chromosome-specific aneuploidy. Centromeres are key elements for the maintenance of chromosome segregation fidelity via a specialized chromatin marked by CENP-A wrapped by repetitive DNA. These long stretches of repetitive DNA vary in length among human chromosomes. Using CENP-A genetic inactivation in human cells, we directly interrogate if differences in the centromere length reflect the heterogeneity of centromeric DNA-dependent features and whether this, in turn, affects the genesis of chromosome-specific aneuploidy. Using three distinct approaches, we show that mis-segregation rates vary among different chromosomes under conditions that compromise centromere function. Whole-genome sequencing and centromere mapping combined with cytogenetic analysis, small molecule inhibitors, and genetic manipulation revealed that inter-chromosomal heterogeneity of centromeric features, but not centromere length, influences chromosome segregation fidelity. We conclude that faithful chromosome segregation for most of human chromosomes is biased in favor of centromeres with high abundance of DNA-dependent centromeric components. These inter-chromosomal differences in centromere features can translate into non-random aneuploidy, a hallmark of cancer and genetic diseases.

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“…As direct implantation of tissue fragments to rodent brains is challenging, GBM orthotopic xenografts usually rely on single cell dissociation followed by in vitro cultures prior to xenotransplantation 51,66,[68][69][70] , where cultures are often maintained for unspecified time and passage number. To minimize the loss of tissue architecture and heterogeneity, which may lead to clonal selection and adaptation 71,72 , we derive organoids from mechanically minced glioma tissue, which is only briefly maintained in culture without any in vitro passaging. This process retains the primary nature of GBM cells and as a result it does not allow for indefinite growth of organoids in vitro as seen under serum-free conditions 29 .…”

Section: Discussionmentioning

confidence: 99%

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Golebiewska

Hau

Oudin

et al. 2020

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Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies.

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Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids

Cited by 185 publications

References 69 publications

Degree and site of chromosomal instability define its oncogenic potential

Degree and site of chromosomal instability define its oncogenic potential

Human chromosome‐specific aneuploidy is influenced by DNA ‐dependent centromeric features

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

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