A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity

Sachs, Norman; Ligt, Joep de; Kopper, Oded; Gogola, Ewa; Bounova, Gergana; Weeber, Fleur; Balgobind, Anjali Vanita; Wind, Karin; Gračanin, Ana Gudelj; Begthel, Harry; Korving, Jeroen; Boxtel, Ruben van; Duarte, Alexandra A.; Lelieveld, Daphne; Hoeck, Arne van; Ernst, Robert F; Blokzijl, Francis; Nijman, Isaäc J.; Hoogstraat, Marlous; Ven, Marieke van der; Egan, David A.; Zinzalla, Vittoria; Moll, Jürgen; Boj, Sylvia F.; Voest, Emile E.; Wessels, Lodewyk; Diest, Paul J. van; Rottenberg, Sven; Vries, Robert G.J.; Cuppen, Edwin; Clevers, Hans

doi:10.1016/j.cell.2017.11.010

Cited by 1,227 publications

(1,209 citation statements)

References 70 publications

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“…(Toolan, ; Taetle et al , ; Fu et al , ; Beckhove et al , ; Fichtner et al , ; Shultz et al , ; Wang et al , ; Cutz et al , ; Sato et al , , ; Hennessey et al , ; Gao et al , ; Karthaus et al , ; Boj et al , ; Lee et al , ; Li et al , , ; Sachs et al , ; Yan et al , ; Kopper et al , ; Schutgens et al , ).…”

Section: Introductionunclassified

Xenograft and organoid model systems in cancer research

et al. 2019

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Patient‐derived tumour xenografts and tumour organoids have become important preclinical model systems for cancer research. Both models maintain key features from their parental tumours, such as genetic and phenotypic heterogeneity, which allows them to be used for a wide spectrum of applications. In contrast to patient‐derived xenografts, organoids can be established and expanded with high efficiency from primary patient material. On the other hand, xenografts retain tumour–stroma interactions, which are known to contribute to tumorigenesis. In this review, we discuss recent advances in patient‐derived tumour xenograft and tumour organoid model systems and compare their promises and challenges as preclinical models in cancer research.

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Section: Introductionunclassified

Xenograft and organoid model systems in cancer research

et al. 2019

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“…Organoids are 3D models of primary tumor tissue obtained from fresh biopsies, which are generated by partial mechanical or enzymatic digestion before embedding the resulting small tumor pieces in an extracellular matrix, such as Matrigel. Recently, 3D organoids were shown to be propagated in Matrigel from various cancer types, including breast, colon, pancreatic, ovarian and prostate cancers . While success rates of organoid establishment clearly appear to vary by tumor grade and cancer type, several studies reported that tumor‐derived 3D‐organoids propagated in Matrigel retain the histological and genetic features of the originating tumors and recapitulate drug responses observed in matched patients .…”

Section: Discussionmentioning

confidence: 99%

Reflection of neuroblastoma intratumor heterogeneity in the new OHC‐NB1 disease model

Thole

Toedling

Sprüssel

et al. 2019

Intl Journal of Cancer

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Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC‐NB1, from a bone marrow metastasis from a patient diagnosed with MYCN‐amplified neuroblastoma and performed whole‐exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC‐NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single‐nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC‐NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.

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“…Current efforts to characterize these cultures as tumor models has highlighted their potential in study and evaluation of their representative patients (25–28). The ability to grow these primary tumors in vitro , enables a more high-throughput screening of individual patient tumors for sensitivity to drugs already approved for clinical use or under clinical evaluation.…”

Section: Integrating Mouse Studies With Clinical Carementioning

confidence: 99%

The Mouse Hospital and Its Integration in Ultra-Precision Approaches to Cancer Care

Clohessy

Pandolfi

2018

Front. Oncol.

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Precision medicine holds real promise for the treatment of cancer. Adapting therapeutic strategies so patients receive individualized treatment protocols, will transform how diseases like cancer are managed. Already, molecular profiling technologies have provided unprecedented capacity to characterize tumors, yet the ability to translate this to actionable outcome in the clinic is limited. To enable real time translation of personalized therapeutic approaches to patient care in a co-clinical manner will require the adoption and integration of approaches that facilitate modeling of patient disease. The Mouse Hospital represents an approach that is ideally suited to pre- and co-clinical evaluation of novel therapeutic strategies for clinical care. Patient derived xenograft (PDX) technologies and in situ tumor modeling approaches using genetically engineered mouse models (GEMMs) already have a proven capacity to mimic human tumor responses, and their application can deliver invaluable insights into appropriate clinical approaches for individual patients by mirroring human clinical trials using a Co-Clinical Trial project and Mouse Hospital infrastructure. Additionally, the integration of the Mouse Hospital with other emerging technologies for the application of precision medicines, including organoid technologies, provides a platform that enables medical centers to truly reap the benefits that precision medicine has to offer.

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A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity

Cited by 1,227 publications

References 70 publications

Xenograft and organoid model systems in cancer research

Xenograft and organoid model systems in cancer research

Reflection of neuroblastoma intratumor heterogeneity in the new OHC‐NB1 disease model

The Mouse Hospital and Its Integration in Ultra-Precision Approaches to Cancer Care

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