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

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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Publication Details

Journal
Nature Biomedical Engineering
Published
2024-12-10
DOI
https://doi.org/10.1038/s41551-024-01273-9
Citations
24
Primary Topic
Pancreatic and Hepatic Oncology Research
Type
article
Field-Weighted Citation Impact
6.78

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article

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

Georgios Kaissis, Katja Steiger, Anja Zeigerer, Till Richter et al.
24 citations
Nature Biomedical Engineering
Pancreatic and Hepatic Oncology Research
6.78
article

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

Georgios Kaissis, Katja Steiger, Anja Zeigerer, Till Richter, Carlo H. Maurer, Rickmer Braren, Christina Scheel, Maximilian Schuster, Thomas J. Metzler, Sophie Dobiasch, Stefanie Bärthel, Thomas Engleitner, Irina Heid, Aristeidis Papargyriou, Katja Peschke, Andreas R. Bausch, Christian Schneeweis, Moritz Knolle, Sebastian Lange, Roland M. Schmid, S. Ravichandran, Aditi Shastri, Rupert Öllinger, Laura Mataite, Hellen Ishikawa‐Ankerhold, Surui Wang, Malte D. Luecken, Jacco van Rheenen, Jeff S. Jasper, Stephanie Elisabeth Combs, Hendrik A. Messal, Maximilian Reichert, Aashreya Ravichandra, Roland Rad, Fabian Joachim Theis, Günter Schneider, Arlett Schäfer, David P. Cook, Dieter Saur, Hussein Trabulssi, Sebastian Mueller, Laura Schmidleitner, Mulham Najajreh, Mariia Semina
article en
24 citations

Abstract

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.

Nature Biomedical EngineeringVol. 9(6)
University of Ottawa (CA), German Cancer Research Center (DE), Center for Integrated Protein Science Munich (DE), Heidelberg University (DE), Ottawa Hospital (CA), University Hospital Heidelberg (DE), Wellcome Sanger Institute (GB), TUM Klinikum (DE), The Netherlands Cancer Institute (NL), Helmholtz Zentrum München (DE), Oncode Institute (NL), Universitätsmedizin Göttingen (DE), Centre de Coopération Universitaire Franco-Bavarois (DE), Diabetesinstitut Heidelberg (DE), Deutsches Diabetes-Zentrum e.V. (DE), German Center for Diabetes Research (DE), Ottawa Hospital Research Institute (CA), Deutsches Konsortium für Translationale Krebsforschung (DE), Munich Center for Machine Learning, Heinrich Heine University Düsseldorf (DE), Imperial College London (GB), Technical University of Munich (DE), Ludwig-Maximilians-Universität München (DE), Ruhr University Bochum (DE)
Deutscher Akademischer Austauschdienst, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Technische Universität München, Deutsche Krebshilfe, Klaus Tschira Stiftung, European Association for the Study of the Liver, Deutschen Konsortium für Translationale Krebsforschung
Good health and well-being
Openalex Percentile: Top 2%
Pancreatic and Hepatic Oncology Research
6.78
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