@article{afc9c18e213c4908b97c7e03ffdf748e,
title = "ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis",
abstract = "Pancreatic adenocarcinoma (PDA) is an aggressive disease driven by oncogenic KRAS and characterized by late diagnosis and therapeutic resistance. Here we show that deletion of the ataxia-telangiectasia group D-comple-menting (Atdc) gene, whose human homolog is up-regulated in the majority of pancreatic adenocarcinoma, completely prevents PDA development in the context of oncogenic KRAS. ATDC is required for KRAS-driven ac-inar–ductal metaplasia (ADM) and its progression to pancreatic intraepithelial neoplasia (PanIN). As a result, mice lacking ATDC are protected from developing PDA. Mechanistically, we show ATDC promotes ADM progression to PanIN through activation of β-catenin signaling and subsequent SOX9 up-regulation. These results provide new insight into PDA initiation and reveal ATDC as a potential target for preventing early tumor-initiating events.",
keywords = "ATDC, Acinar-to-ductal metaplasia, KRAS, PanIN lesion, Pancreatic ductal adenocarcinoma, SOX9, TRIM29, β-catenin]",
author = "Lidong Wang and Huibin Yang and Andrea Zamperone and Daniel Diolaiti and Palmbos, {Phillip L.} and Abel, {Ethan V.} and Vinee Purohit and Igor Dolgalev and Rhim, {Andrew D.} and Mats Ljungman and Hadju, {Christina H.} and Halbrook, {Christopher J.} and Dafna Bar-Sagi and {Di Magliano}, {Marina Pasca} and Crawford, {Howard C.} and Simeone, {Diane M.}",
note = "Funding Information: We thank members of the Simeone laboratory for technical assistance and helpful discussions. We appreciate the help of the Howard Crawford laboratory and Dafna Bar-Sagi laboratory in sharing technical advice in establishing the acinar 3D cultures and in use of the K-RASG12D PDECs. This work was supported by funding from the National Cancer Institute (grants 2R01CA131045 and 1R01CA174836 to D.M.S.) and the Sky Foundation (to D.M.S. and H.C.C.) Author contributions: L.W., H.Y., A.Z., M.L., C.H.H., C.J.H., I.D., H.C.C., and D.M.S. devised and performed the experiments, analyzed the results, and prepared the manuscript. P.L.P., E.V.A., V.P., A.D.R., D.B.-S., M.P.d.M., and D.D. provided reagents and expertise, helped prepare the manuscript, and provided feedback. Publisher Copyright: {\textcopyright} 2019 Wang et al.",
year = "2019",
month = jun,
day = "1",
doi = "10.1101/gad.323303.118",
language = "English (US)",
volume = "33",
pages = "641--655",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "11-12",
}