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Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia

Oncogene volume 32, pages 1950–1958 (2013)Cite this article

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers owing to a number of characteristics including difficulty in establishing early diagnosis and the absence of effective therapeutic regimens. A large number of genetic alterations have been ascribed to PDAC with mutations in the KRAS2 proto-oncogene thought to be an early event in the progression of disease. Recent lineage-tracing studies have shown that acinar cells expressing mutant KrasG12D are induced to transdifferentiate, generating duct-like cells through a process known as acinar-ductal metaplasia (ADM). ADM lesions then convert to precancerous pancreatic intraepithelial neoplasia (PanIN) that progresses to PDAC over time. Thus, understanding the earliest events involved in ADM/PanIN formation would provide much needed information on the molecular pathways that are instrumental in initiating this disease. As studying the transition of acinar cells to metaplastic ductal cells in vivo is complicated by analysis of the entire organ, an in vitro three dimensional (3D) culture system was used to model ADM outside the animal. KrasG12D-expressing acinar cells rapidly underwent ADM in 3D culture, forming ductal cysts that silenced acinar genes and activated duct genes, characteristics associated with in vivo ADM/PanIN lesions. Analysis of downstream KRAS signaling events established a critical importance for the Raf/MEK/ERK pathway in ADM induction. In addition, forced expression of the acinar-restricted transcription factor Mist1, which is critical to acinar cell organization, significantly attenuated KrasG12D-induced ADM/PanIN formation. These results suggest that maintaining MIST1 activity in KrasG12D-expressing acinar cells can partially mitigate the transformation activity of oncogenic KRAS. Future therapeutics that target both the MAPK pathway and Mist1 transcriptional networks may show promising efficacy in combating this deadly disease.

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Acknowledgements

We thank Judy Hallett of the Purdue Center for Cancer Research Transgenic Mouse Core Facility for generating the transgenic mouse strains used in this study and David Hess and Anju Karki for critical reading of the manuscript. This work was supported by grants to SFK (NIH CA124586, NIH DK55489 and the Phi Beta Psi Sorority for Cancer Research) and to DD (CTSI Predoctoral Fellowship).

Author contributions: GS, DD, CQ, DB and DM designed and performed experiments; SFK designed and analyzed experiments and GS and SFK wrote the manuscript.

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  1. G Shi, D DiRenzo and C Qu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA

    G Shi, D DiRenzo, C Qu, D Barney, D Miley & S F Konieczny

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Correspondence to S F Konieczny.

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Shi, G., DiRenzo, D., Qu, C. et al. Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia. Oncogene 32, 1950–1958 (2013). https://doi.org/10.1038/onc.2012.210

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