Plate IV.119 · Publications
Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma
Article in Nature Biomedical Engineering, 10 December 2024.
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.
Cite
@article{papargyriou2024heterogeneity,
title = {{Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma}},
author = {Papargyriou, Aristeidis and Najajreh, Mulham and Cook, David P. and Maurer, Carlo H. and Bärthel, Stefanie and Messal, Hendrik A. and Ravichandran, Sakthi K. and Richter, Till and Knolle, Moritz and Metzler, Thomas and Shastri, Akul R. and Öllinger, Rupert and Jasper, Jacob and Schmidleitner, Laura and Wang, Surui and Schneeweis, Christian and Ishikawa-Ankerhold, Hellen and Engleitner, Thomas and Mataite, Laura and Semina, Mariia and Trabulssi, Hussein and Lange, Sebastian and Ravichandra, Aashreya and Schuster, Maximilian and Mueller, Sebastian and Peschke, Katja and Schäfer, Arlett and Dobiasch, Sophie and Combs, Stephanie E. and Schmid, Roland M. and Bausch, Andreas R. and Braren, Rickmer and Heid, Irina and Scheel, Christina H. and Schneider, Günter and Zeigerer, Anja and Luecken, Malte D. and Steiger, Katja and Kaissis, Georgios and van Rheenen, Jacco and Theis, Fabian J. and Saur, Dieter and Rad, Roland and Reichert, Maximilian},
journal = {Nature Biomedical Engineering},
publisher = {Springer Science and Business Media LLC},
year = {2024},
month = dec,
doi = {10.1038/s41551-024-01273-9},
url = {https://doi.org/10.1038/s41551-024-01273-9},
pmid = {39658630},
pmcid = {PMC12176653}
}