| First Author | Beel S | Year | 2020 |
| Journal | Nat Commun | Volume | 11 |
| Issue | 1 | Pages | 3409 |
| PubMed ID | 32641778 | Mgi Jnum | J:295341 |
| Mgi Id | MGI:6448017 | Doi | 10.1038/s41467-020-17226-0 |
| Citation | Beel S, et al. (2020) kappaB-Ras and Ral GTPases regulate acinar to ductal metaplasia during pancreatic adenocarcinoma development and pancreatitis. Nat Commun 11(1):3409 |
| abstractText | Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and therapy resistance. Here, we show that low expression of kappaB-Ras GTPases is frequently detected in PDAC and correlates with higher histologic grade. In a model of KRas(G12D)-driven PDAC, loss of kappaB-Ras accelerates tumour development and shortens median survival. kappaB-Ras deficiency promotes acinar-to-ductal metaplasia (ADM) during tumour initiation as well as tumour progression through intrinsic effects on proliferation and invasion. kappaB-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 kappaB-Ras proteins and highlight low kappaB-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. |
