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Papargyriou, A. ; Najajreh, M.* ; Cook, D.P.* ; Maurer, C.H.* ; Bärthel, S.* ; Messal, H.A.* ; Ravichandran, S.K.* ; Richter, T. ; Knolle, M.* ; Metzler, T.* ; Shastri, A.R.* ; Öllinger, R.* ; Jasper, J.* ; Schmidleitner, L.* ; Wang, S. ; Schneeweis, C.* ; Ishikawa-Ankerhold, H.* ; Engleitner, T.* ; Mataite, L.* ; Semina, M.* ; Trabulssi, H.* ; Lange, S.* ; Ravichandra, A.* ; Schuster, M.* ; Mueller, S.* ; Peschke, K.* ; Schäfer, A.* ; Dobiasch, S. ; Combs, S.E. ; Schmid, R.M.* ; Bausch, A.R.* ; Braren, R.* ; Heid, I.* ; Scheel, C. ; Schneider, G.* ; Zeigerer, A. ; Luecken, M. ; Steiger, K.* ; Kaissis, G. ; van Rheenen, J.* ; Theis, F.J. ; Saur, D.* ; Rad, R.* ; Reichert, M.*

Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma.

Nat. Bio. Eng., DOI: 10.1038/s41551-024-01273-9 (2024)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
In patients with pancreatic ductal adenocarcinoma (PDAC), intratumoural and intertumoural heterogeneity increases chemoresistance and mortality rates. However, such morphological and phenotypic diversities are not typically captured by organoid models of PDAC. Here we show that branched organoids embedded in collagen gels can recapitulate the phenotypic landscape seen in murine and human PDAC, that the pronounced molecular and morphological intratumoural and intertumoural heterogeneity of organoids is governed by defined transcriptional programmes (notably, epithelial-to-mesenchymal plasticity), and that different organoid phenotypes represent distinct tumour-cell states with unique biological features in vivo. We also show that phenotype-specific therapeutic vulnerabilities and modes of treatment-induced phenotype reprogramming can be captured in phenotypic heterogeneity maps. Our methodology and analyses of tumour-cell heterogeneity in PDAC may guide the development of phenotype-targeted treatment strategies.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Stem-cell; Cancer; Tumor; Subtypes; Inference; Emt
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 2157-846X
e-ISSN 2157-846X
Zeitschrift Nature biomedical engineering
Verlag Nature Publishing Group
Verlagsort London ; New York NY ; Tokyo
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Stem Cell Research (ISF)
Institute of Computational Biology (ICB)
Institute of Diabetes and Cancer (IDC)
Institute of Radiation Medicine (IRM)
Institute for Machine Learning in Biomed Imaging (IML)
Institute of Lung Health and Immunity (LHI)
POF Topic(s) 30204 - Cell Programming and Repair
30205 - Bioengineering and Digital Health
90000 - German Center for Diabetes Research
30203 - Molecular Targets and Therapies
80000 - German Center for Lung Research
Forschungsfeld(er) Stem Cell and Neuroscience
Enabling and Novel Technologies
Helmholtz Diabetes Center
Radiation Sciences
Lung Research
PSP-Element(e) G-500800-001
G-503800-001
G-501900-254
G-501300-001
G-500890-001
G-507100-001
G-501800-833
Förderungen Klaus Tschira Foundation
German Scholars Organization
DKTK (German Cancer Consortium)
BMBF
Bavarian Ministry of Economic Affairs, EISglobe
German Research Foundation (DFG)
German Cancer Aid (Max Eder Program, Deutsche Krebshilfe)
Netherlands Organization of Scientific Research NWO

German Federal Ministry of Education and Research
European Association for the Study of the Liver
Federal Ministry of Education and Research
DAAD programme Konrad Zuse Schools of Excellence in Artificial Intelligence
Helmholtz Association under the joint research school 'Munich School for Data Science'-MUDS
BZKF Study Group - Pancreatic Cancer
DOI 10.1038/s41551-024-01273-9
WOS ID 001374565000001
Scopus ID 85212196678
PubMed ID 39658630
Erfassungsdatum 2024-12-12
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