κB-Ras and Ral GTPases regulate acinar to ductal metaplasia during pancreatic adenocarcinoma development and pancreatitis.

Beel S, Kolloch L, Apken LH, Jürgens L, Bolle A, Sudhof N, Ghosh S, Wardelmann E, Meisterernst M, Steinestel K, Oeckinghaus A

Forschungsartikel (Zeitschrift) | Peer reviewed

Zusammenfassung

Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and therapy resistance. Here, we show that low expression of $κ$B-Ras GTPases is frequently detected in PDAC and correlates with higher histologic grade. In a model of KRasG12D-driven PDAC, loss of $κ$B-Ras accelerates tumour development and shortens median survival. $κ$B-Ras deficiency promotes acinar-to-ductal metaplasia (ADM) during tumour initiation as well as tumour progression through intrinsic effects on proliferation and invasion. $κ$B-Ras proteins are also required for acinar regeneration after pancreatitis, demonstrating a general role in control of plasticity. Molecularly, upregulation of Ral GTPase activity and Sox9 expression underlies the observed phenotypes, identifying a previously unrecognized function of Ral signalling in ADM. Our results provide evidence for a tumour suppressive role of $κ$B-Ras proteins and highlight low $κ$B-Ras levels and consequent loss of Ral control as risk factors, thus emphasizing the necessity for therapeutic options that allow interference with Ral-driven signalling.

Details zur Publikation

FachzeitschriftNature Communications
Jahrgang / Bandnr. / Volume11
Ausgabe / Heftnr. / Issue1
StatusVeröffentlicht
Veröffentlichungsjahr2020
DOI10.1038/s41467-020-17226-0
Link zum Volltexthttp://www.nature.com/articles/s41467-020-17226-0 http://www.ncbi.nlm.nih.gov/pubmed/32641778 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC7343838
Stichwörterpanncreatic cancer; Ral GTPases; kappaB-Ras; acinar-to-ductal metaplasia

Autor*innen der Universität Münster

Apken, Lisa Helene
Institut für Molekulare Tumorbiologie
Oeckinghaus, Andrea Marion
Institut für Molekulare Tumorbiologie