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Mameishvili, E. ; Serafimidis, I.* ; Iwaszkiewicz, S. ; Lesche, M. ; Reinhardt, S.* ; Bölicke, N. ; Büttner, M. ; Stellas, D.* ; Papadimitropoulou, A.* ; Szabolcs, M.* ; Anastassiadis, K.* ; Dahl, A.* ; Theis, F.J. ; Efstratiadis, A.* ; Gavalas, A.

Aldh1b1 expression defines progenitor cells in the adult pancreas and is required for Kras-induced pancreatic cancer.

Proc. Natl. Acad. Sci. U.S.A. 116, 20679-20688 (2019)
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The presence of progenitor or stem cells in the adult pancreas and their potential involvement in homeostasis and cancer development remain unresolved issues. Here, we show that mouse centroacinar cells can be identified and isolated by virtue of the mitochondrial enzyme Aldh1b1 that they uniquely express. These cells are necessary and sufficient for the formation of self-renewing adult pancreatic organoids in an Aldh1b1-dependent manner. Aldh1b1-expressing centroacinar cells are largely quiescent, self-renew, and, as shown by genetic lineage tracing, contribute to all 3 pancreatic lineages in the adult organ under homeostatic conditions. Single-cell RNA sequencing analysis of these cells identified a progenitor cell population, established its molecular signature, and determined distinct differentiation pathways to early progenitors. A distinct feature of these progenitor cells is the preferential expression of small GTPases, including Kras, suggesting that they might be susceptible to Kras-driven oncogenic transformation. This finding and the overexpression of Aldh1b1 in human and mouse pancreatic cancers, driven by activated Kras, prompted us to examine the involvement of Aldh1b1 in oncogenesis. We demonstrated genetically that ablation of Aldh1b1 completely abrogates tumor development in a mouse model of Kras(G12D)-induced pancreatic cancer.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Adult Stem And Progenitor Cells ; Aldehyde Dehydrogenase ; Organoids ; Single-cell Rna Sequencing ; Pancreatic Ductal Adenocarcinoma; Aldehyde Dehydrogenase 1b1; Beta-cells; Centroacinar Cells; Exocrine Cells; Oncogenic Kras; Acinar-cells; Ductal Cells; Stem-cells; Endocrine; Differentiation
Language english
Publication Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 116, Issue: 41, Pages: 20679-20688 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Publishing Place 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Pancreatic Islet Research (IPI)
Institute of Computational Biology (ICB)
POF-Topic(s) 90000 - German Center for Diabetes Research
30205 - Bioengineering and Digital Health
Research field(s) Helmholtz Diabetes Center
Enabling and Novel Technologies
PSP Element(s) G-502600-003
G-503800-001
DOI 10.1073/pnas.1901075116
WOS ID WOS:000489770700063
Scopus ID 85073073758
PubMed ID 31548432
Erfassungsdatum 2019-09-26
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