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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 Gold (Paid Option)
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
Korrespondenzautor
Schlagwörter Stem-cell; Cancer; Tumor; Subtypes; Inference; Emt
ISSN (print) / ISBN 2157-846X
e-ISSN 2157-846X
Zeitschrift Nature biomedical engineering
Verlag Nature Publishing Group
Verlagsort London ; New York NY ; Tokyo
Nichtpatentliteratur Publikationen
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)
Lung Health and Immunity (LHI)
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