TY - JOUR
T1 - Aldh1b1 expression defines progenitor cells in the adult pancreas and is required for Kras-induced pancreatic cancer
AU - Mameishvili, Ekaterina
AU - Serafimidis, Ioannis
AU - Iwaszkiewicz, Sara
AU - Lesche, Mathias
AU - Reinhardt, Susanne
AU - Bölicke, Nora
AU - Büttner, Maren
AU - Stellas, Dimitris
AU - Papadimitropoulou, Adriana
AU - Szabolcs, Matthias
AU - Anastassiadis, Konstantinos
AU - Dahl, Andreas
AU - Theis, Fabian
AU - Efstratiadis, Argiris
AU - Gavalas, Anthony
N1 - Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/10/8
Y1 - 2019/10/8
N2 - 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 KrasG12D-induced pancreatic cancer.
AB - 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 KrasG12D-induced pancreatic cancer.
KW - Adult stem and progenitor cells
KW - Aldehyde dehydrogenase
KW - Organoids
KW - Pancreatic ductal adenocarcinoma
KW - Single-cell RNA sequencing
UR - http://www.scopus.com/inward/record.url?scp=85073073758&partnerID=8YFLogxK
U2 - 10.1073/pnas.1901075116
DO - 10.1073/pnas.1901075116
M3 - Article
C2 - 31548432
AN - SCOPUS:85073073758
SN - 0027-8424
VL - 116
SP - 20679
EP - 20688
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 41
ER -
