Reference : Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas ...
Scientific journals : Article
Life sciences : Genetics & genetic processes
Human health sciences : Neurology
Human health sciences : Oncology
Systems Biomedicine
http://hdl.handle.net/10993/44421
Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology.
English
Golebiewska, Anna mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > >]
Hau, Ann-Christin [> >]
Oudin, Anaïs [> >]
Stieber, Daniel [> >]
Yabo, Yahaya A. [> >]
Baus, Virginie [> >]
Barthelemy, Vanessa [> >]
Klein, Eliane [> >]
Bougnaud, Sébastien [> >]
Keunen, Olivier [> >]
Wantz, May [> >]
Michelucci, Alessandro mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Neirinckx, Virginie [> >]
Muller, Arnaud [> >]
Kaoma, Tony [> >]
Nazarov, Petr V. [> >]
Azuaje, Francisco mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) >]
De Falco, Alfonso [> >]
Flies, Ben [> >]
Richart, Lorraine [> >]
Poovathingal, Suresh [> >]
Arns, Thais mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Grzyb, Kamil mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Mock, Andreas [> >]
Herold-Mende, Christel [> >]
Steino, Anne [> >]
Brown, Dennis [> >]
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Miletic, Hrvoje [> >]
Malta, Tathiane M. [> >]
Noushmehr, Houtan [> >]
Kwon, Yong-Jun mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Jahn, Winnie [> >]
Klink, Barbara [> >]
Tanner, Georgette [> >]
Stead, Lucy F. [> >]
Mittelbronn, Michel mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Skupin, Alexander mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Hertel, Frank mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Bjerkvig, Rolf [> >]
Niclou, Simone mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) >]
3-Oct-2020
Acta Neuropathologica
Yes (verified by ORBilu)
International
0001-6322
1432-0533
Germany
[en] Glioblastoma ; Glioma ; Glioma recurrence ; IDH1 ; MGMT ; Organoid ; Patient-derived orthotopic xenograft ; Precision medicine ; Preclinical models ; VAL-083
[en] Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) ; Departmanet of Life Sciences and Medicine ; Luxembourg Centre for Systems Biomedicine (LCSB): Neuropathology (Mittelbronn Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Interventional Neuroscience (Hertel Group)
n°7.4615.18/Télévie-FNRS ; n°7.4632.17/Télévie-FNRS ; 766069/H2020 Marie Skłodowska-Curie Actions ; Pan-RTK/Fondation Cancer Luxembourg ; PEARL award - P16/BM/11192868/Fonds National de la Recherche Luxembourg ; C17/BM/11664971 FNR
Researchers ; Professionals ; Students ; General public
http://hdl.handle.net/10993/44421
10.1007/s00401-020-02226-7
https://link.springer.com/article/10.1007/s00401-020-02226-7

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