BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance

Duarte, Alexandra A.; Gogola, Ewa; Sachs, Norman; Barazas, Marco; Annunziato, Stefano; Ruiter, Julian R. de; Velds, Arno; Blatter, Sohvi; Houthuijzen, Julia M.; Ven, Marieke van de; Clevers, Hans; Borst, Piet; Jonkers, Jos; Rottenberg, Sven

doi:10.1038/nmeth.4535

Cited by 119 publications

(132 citation statements)

References 40 publications

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“…S1B). Since these drug-response profiles are consistent with restored HR and resemble KB1P tumors that have lost 53BP1 (7,14), we analyzed 53BP1 expression by IHC in a panel of KB1P-RR tumors. Interestingly, while PARPi resistance was mediated by loss of 53BP1 expression in 12 out of 79 KB1P(M) tumors ( (7); data not shown), all 26 KB1P-RR tumors retained 53BP1 expression (p = 0.0253, binomial test) ( Supplementary Fig.…”

Section: Restorationmentioning

confidence: 90%

“…single dose (12)) or untreated. To assess the radiotherapy response in isogenic Trp53bp1-knockout or control tumors (sgNT), previously generated and validated tumor organoids were allografted in 6-9 week old NMRI nude female mice, as described (14).…”

Section: In Vivo Studiesmentioning

confidence: 99%

“…Briefly, cells were cultured in DMEM/F-12 medium (Life Technologies) in the presence of 10% FCS, penicillin/streptomycin (Gibco), 5μg/mL insulin (Sigma), 5ng/mL epidermal growth factor (Life Technologies) and 5ng/mL cholera toxin (Gentaur) under low oxygen conditions (3% O 2 , 5% CO 2 at 37 o C). The KB1PM7-N 3D tumor organoid lines were previously established from a Brca1 -/-;p53 -/-;Mdr1a/b -/mouse mammary tumor and cultured as described (14).Briefly, KB1PM7-N 3D tumor organoid cells were seeded in Basement Membrane Extract Type 2 (BME, Trevigen) on 24-well suspension plates (Greiner Bio-One) and cultured in AdDMEM/F12 supplemented with 1 M HEPES (Sigma), GlutaMAX (Invitrogen), penicillin/streptomycin (Gibco), B27 (Gibco), 125 µM Nacetyl-L-cysteine (Sigma), 50 ng/mL murine epidermal growth factor (Invitrogen).…”

Section: Cell Culturementioning

confidence: 99%

“…Doxycycline was removed from the medium prior to starting the competition assay. The KB1PM7-N 3D tumor organoid line derivatives KB1PM7-N sgNT and KB1PM7-N sgTrp53bp1 were established previously (14).…”

Section: Plasmids and Genome Editingmentioning

confidence: 99%

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Radiosensitivity is an acquired vulnerability of PARPi-resistant BRCA1-deficient tumors

Barazas

Gasparini

Huang

et al. 2018

Preprint

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The homologous recombination (HR) defect in BRCA1-associated cancers can be therapeutically exploited by the treatment with DNA-damaging agents and poly (ADPribose) polymerase (PARP) inhibitors. We and others previously reported that BRCA1deficient tumors are initially hypersensitive to the inhibition of topoisomerase I/II and PARP, but acquire drug resistance through restoration of HR activity by the loss of endresection antagonists of the 53BP1/RIF1/REV7/Shieldin/CST pathway. Here, we identified radiotherapy as an acquired vulnerability of 53BP1;BRCA1-deficient cells in vitro and in vivo. In contrast to the radioresistance caused by HR restoration through BRCA1 reconstitution, HR restoration by 53BP1 pathway inactivation further increases radiosensitivity. This highlights the relevance of this pathway for the repair of radiotherapy-induced damage. Moreover, our data show that BRCA1-mutated tumors -2 -that acquired drug resistance due to BRCA1-independent HR restoration can be targeted by radiotherapy. STATEMENT OF SIGNIFICANCEIn this study, we uncovered radiosensitivity as a novel therapeutically exploitable vulnerability of BRCA1-deficient mouse mammary cells that have acquired drug resistance due to the loss of the 53BP1 pathway.

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Section: Restorationmentioning

confidence: 90%

Section: In Vivo Studiesmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Plasmids and Genome Editingmentioning

confidence: 99%

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Radiosensitivity is an acquired vulnerability of PARPi-resistant BRCA1-deficient tumors

Barazas

Gasparini

Huang

et al. 2018

Preprint

Self Cite

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“…In addition, human organoid cultures can be utilized for the development of PDX tumors in vivo . and organoids derived from mouse primary tissues and cell types can provide useful models for human cancer (29–31). Thus, organoid approaches can facilitate with evaluation of tumor sensitivity to therapeutic agents, and enable the testing of multiple combinations of therapeutic agents to identify potential therapeutic strategies for the treatment of individual cancers.…”

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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Patient‐Derived Organoids Can Guide Personalized‐Therapies for Patients with Advanced Breast Cancer

et al. 2021

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Most breast cancers at an advanced stage exhibit an aggressive nature, and there is a lack of effective anticancer options. Herein, the development of patient-derived organoids (PDOs) is described as a real-time platform to explore the feasibility of tailored treatment for refractory breast cancers. PDOs are successfully generated from breast cancer tissues, including heavily treated specimens. The microtubule-targeting drug-sensitive response signatures of PDOs predict improved distant relapse-free survival for invasive breast cancers treated with adjuvant chemotherapy. It is further demonstrated that PDO pharmaco-phenotyping reflects the previous treatment responses of the corresponding patients. Finally, as clinical case studies, all patients who receive at least one drug predicate to be sensitive by PDOs achieve good responses. Altogether, the PDO model is developed as an effective platform for evaluating patient-specific drug sensitivity in vitro, which can guide personal treatment decisions for breast cancer patients at terminal stage.

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BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance

Cited by 119 publications

References 40 publications

Radiosensitivity is an acquired vulnerability of PARPi-resistant BRCA1-deficient tumors

Radiosensitivity is an acquired vulnerability of PARPi-resistant BRCA1-deficient tumors

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

Patient‐Derived Organoids Can Guide Personalized‐Therapies for Patients with Advanced Breast Cancer

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