MECOM permits pancreatic acinar cell dedifferentiation avoiding cell death under stress conditions

Elyne Backx, Elke Wauters, Jonathan Baldan, Mathias Van Bulck, Ellis Michiels, Yves Heremans, Diedert Luc De Paep, Mineo Kurokawa, Susumu Goyama, Luc Bouwens, Patrick Jacquemin, Isabelle Houbracken, Ilse Rooman

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15 Citaten (Scopus)
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Samenvatting

Maintenance of the pancreatic acinar cell phenotype suppresses tumor formation. Hence, repetitive acute or chronic pancreatitis, stress conditions in which the acinar cells dedifferentiate, predispose for cancer formation in the pancreas. Dedifferentiated acinar cells acquire a large panel of duct cell specific markers. However, it remains unclear to what extent dedifferentiated acini differ from native duct cells and which genes are uniquely regulating acinar cell dedifferentiation. Moreover, most studies have been performed in mouse since the availability of human cells is scarce.

Here, we applied a non-genetic lineage tracing method in our culture model of human pancreatic exocrine cells that allowed cell-type specific gene expression profiling by RNA sequencing. Subsequent to this discovery analysis, one transcription factor that was unique for dedifferentiated acinar cells was functionally characterized using in vitro and in vivo genetic loss-of-function experimental models.

RNA sequencing analysis showed that human dedifferentiated acinar cells expressed genes in ‘Pathways of cancer’ with prominence of the transcription factor MECOM (EVI-1) that was absent from duct cells. During mouse embryonic development, pre-acinar cells transiently expressed MECOM and MECOM was re-expressed in experimental in vivo models of acute and chronic pancreatitis in vivo, conditions in which acinar cells dedifferentiate. MECOM expression correlated with and was directly regulated by SOX9. MECOM loss-of-function in mouse acinar cells in vitro and in vivo impaired cell adhesion resulting in more prominent acinar cell death and suppressed acinar cell dedifferentiation by limiting ERK signaling.

In conclusion, we transcriptionally profiled the two major human pancreatic exocrine cell types, acinar and duct cells, during experimental stress conditions. We provide insights that in dedifferentiated acinar cells, cancer pathways are upregulated in which MECOM is a critical regulator that suppresses acinar cell death by permitting cellular dedifferentiation.
Originele taal-2English
Pagina's (van-tot)2601-2615
Aantal pagina's15
TijdschriftCell Death and Differentiation
Volume28
Nummer van het tijdschrift9
Vroegere onlinedatum24 mrt 2021
DOI's
StatusPublished - sep 2021

Bibliografische nota

Funding Information:
Ethics approval Biospecimens, transcriptomic and clinical data were collected by the Australian Pancreatic Cancer Genome Initiative (APGI, www.pancreaticcancer.net.au), which is supported by an Avner Pancreatic Cancer Foundation Grant (www.avnersfoundation. org.au). Informed consent was obtained from all patients. Use of clinical samples and data were in accordance with national ethical guidelines and regulations in Australia (HREC/11/RPAH/329—Sydney Local Health District—RPA Zone, protocol X11-0220) and in Belgium (UZ Brussel, B.U.N.143201732468). Consent for the use of residual donor material for research was obtained according to the legislation in the country of organ procurement. All animal experiments were approved by the Ethical Committee for Animal Testing at the Vrije Universiteit Brussel (#17-637-1).

Funding Information:
Funding This work was supported by Prijs Kankeronderzoek— Oncologisch Centrum VUB to EB, the Research Foundation Flanders (FWO) (Odysseus project and FWO research project to IR (FWOODYS12 and FWOAL931) and postdoctoral fellowship to IH (FWOTM652)) and European Commission (H2020 681070), granted to the Diabetes Research Center of Vrije Universiteit Brussel.

Publisher Copyright:
© 2021, The Author(s).

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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