RT Journal Article
SR Electronic
T1 Repression of the Type I Interferon Pathway Underlies MYC- and KRAS-Dependent Evasion of NK and B Cells in Pancreatic Ductal Adenocarcinoma
JF Cancer Discovery
JO Cancer Discov
FD American Association for Cancer Research
SP 872
OP 887
DO 10.1158/2159-8290.CD-19-0620
VO 10
IS 6
A1 Muthalagu, Nathiya
A1 Monteverde, Tiziana
A1 Raffo-Iraolagoitia, Ximena
A1 Wiesheu, Robert
A1 Whyte, Declan
A1 Hedley, Ann
A1 Laing, Sarah
A1 Kruspig, Björn
A1 Upstill-Goddard, Rosanna
A1 Shaw, Robin
A1 Neidler, Sarah
A1 Rink, Curtis
A1 Karim, Saadia A.
A1 Gyuraszova, Katarina
A1 Nixon, Colin
A1 Clark, William
A1 Biankin, Andrew V.
A1 Carlin, Leo M.
A1 Coffelt, Seth B.
A1 Sansom, Owen J.
A1 Morton, Jennifer P.
A1 Murphy, Daniel J.
YR 2020
UL http://cancerdiscovery.aacrjournals.org/content/10/6/872.abstract
AB MYC is implicated in the development and progression of pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumor development has been difficult to define. We used modestly elevated expression of human MYC, driven from the Rosa26 locus, to investigate the pancreatic phenotypes arising in mice from an approximation of MYC trisomy. We show that this level of MYC alone suffices to drive pancreatic neuroendocrine tumors, and to accelerate progression of KRAS-initiated precursor lesions to metastatic pancreatic ductal adenocarcinoma (PDAC). Our phenotype exposed suppression of the type I interferon (IFN) pathway by the combined actions of MYC and KRAS, and we present evidence of repressive MYC–MIZ1 complexes binding directly to the promoters of the genes encodiing the type I IFN regulators IRF5, IRF7, STAT1, and STAT2. Derepression of IFN regulator genes allows pancreatic tumor infiltration by B and natural killer (NK) cells, resulting in increased survival.Significance: We define herein a novel mechanism of evasion of NK cell–mediated immunity through the combined actions of endogenously expressed mutant KRAS and modestly deregulated expression of MYC, via suppression of the type I IFN pathway. Restoration of IFN signaling may improve outcomes for patients with PDAC.This article is highlighted in the In This Issue feature, p. 747