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

IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL
Aristeidis Papargyriou, Mulham Najajreh, David P. Cook, Carlo H. Maurer, Stefanie Bärthel, Hendrik A. Messal, Sakthi K. Ravichandran, Till Richter, Moritz Knolle, Thomas Metzler, Akul R. Shastri, Rupert Öllinger, Jacob Jasper, Laura Schmidleitner, Surui Wang, Christian Schneeweis, Hellen Ishikawa-Ankerhold, Thomas Engleitner, Laura Mataite, Mariia Semina, Hussein Trabulssi, Sebastian Lange, Aashreya Ravichandra, Maximilian Schuster, Sebastian Mueller, Katja Peschke, Arlett Schäfer, Sophie Dobiasch, Stephanie E. Combs, Roland M. Schmid, Andreas R. Bausch, Rickmer Braren, Irina Heid, Christina H. Scheel, Günter Schneider, Anja Zeigerer, Malte D. Luecken, Katja Steiger, Georgios Kaissis, Jacco van Rheenen, Fabian J. Theis, Dieter Saur, Roland Rad, Maximilian Reichert
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引用次数: 0

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.

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来源期刊
Nature Biomedical Engineering
Nature Biomedical Engineering Medicine-Medicine (miscellaneous)
CiteScore
45.30
自引率
1.10%
发文量
138
期刊介绍: Nature Biomedical Engineering is an online-only monthly journal that was launched in January 2017. It aims to publish original research, reviews, and commentary focusing on applied biomedicine and health technology. The journal targets a diverse audience, including life scientists who are involved in developing experimental or computational systems and methods to enhance our understanding of human physiology. It also covers biomedical researchers and engineers who are engaged in designing or optimizing therapies, assays, devices, or procedures for diagnosing or treating diseases. Additionally, clinicians, who make use of research outputs to evaluate patient health or administer therapy in various clinical settings and healthcare contexts, are also part of the target audience.
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