Dynamic regulation of expression of KRAS and its effectors determines the ability to initiate tumorigenesis in pancreatic acinar cells

Mohamad Assi, Younes Achouri, Axelle Loriot, Nicolas Dauguet, Hajar Dahou, Jonathan Baldan, Maxime Libert, Jean S Fain, Carmen Guerra, Luc Bouwens, Mariano Barbacid, Frederic P Lemaigre, Patrick Jacquemin

Onderzoeksoutput: Articlepeer review

9 Citaten (Scopus)

Samenvatting

Pancreatic acinar cells are a cell type of origin for pancreatic cancer that become progressively less sensitive to tumorigenesis induced by oncogenic Kras mutations after birth. This sensitivity is increased when Kras mutations are combined with pancreatitis. Molecular mechanisms underlying these observations are still largely unknown. To identify these mechanisms, we generated the first CRISPR-edited mouse models that enable detection of wild-type and mutant KRAS proteins in vivo. Analysis of these mouse models revealed that more than 75% of adult acinar cells are devoid of detectable KRAS protein. In the 25% of acinar cells expressing KRAS protein, transcriptomic analysis highlighted a slight upregulation of the RAS and MAPK pathways. However, at the protein level, only marginal pancreatic expression of essential KRAS effectors, including C-RAF, was observed. The expression of KRAS and its effectors gradually decreased after birth. The low sensitivity of adult acinar cells to Kras mutations resulted from low expression of KRAS and its effectors and the subsequent lack of activation of RAS/MAPK pathways. Pancreatitis triggered expression of KRAS and its effectors as well as subsequent activation of downstream signaling; this induction required the activity of EGFR. Finally, expression of C-RAF in adult pancreas was required for pancreatic tumorigenesis. In conclusion, our study reveals that control of the expression of KRAS and its effectors regulates the sensitivity of acinar cells to transformation by oncogenic Kras mutations.

Originele taal-2English
Pagina's (van-tot)2679-2689
Aantal pagina's11
TijdschriftCancer Research
Volume81
Nummer van het tijdschrift10
Vroegere onlinedatum18 feb 2021
DOI's
StatusPublished - 15 mei 2021

Bibliografische nota

©2021 American Association for Cancer Research.

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