title: PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network.
abstract: Initiation of pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic KRAS mutation, and disease progression is associated with frequent loss of tumor suppressors. In this study, human PDAC genome analyses revealed frequent deletion of the PTEN gene as well as loss of expression in primary tumor specimens. A potential role for PTEN as a haploinsufficient tumor suppressor is further supported by mouse genetic studies. The mouse PDAC driven by oncogenic Kras mutation and Pten deficiency also sustains spontaneous extinction of Ink4a expression and shows prometastatic capacity. Unbiased transcriptomic analyses established that combined oncogenic Kras and Pten loss promotes marked NF-κB activation and its cytokine network, with accompanying robust stromal activation and immune cell infiltration with known tumor-promoting properties. Thus, PTEN/phosphoinositide 3-kinase (PI3K) pathway alteration is a common event in PDAC development and functions in part to strongly activate the NF-κB network, which may serve to shape the PDAC tumor microenvironment.
authors: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Haoqiang
authors: H
authors: Ying
authors: Kutlu G
authors: KG
authors: Elpek
authors: Anant
authors: A
authors: Vinjamoori
authors: Stephanie M
authors: SM
authors: Zimmerman
authors: Gerald C
authors: GC
authors: Chu
authors: Haiyan
authors: H
authors: Yan
authors: Eliot
authors: E
authors: Fletcher-Sananikone
authors: Hailei
authors: H
authors: Zhang
authors: Yingchun
authors: Y
authors: Liu
authors: Wei
authors: W
authors: Wang
authors: Xiaojia
authors: X
authors: Ren
authors: Hongwu
authors: H
authors: Zheng
authors: Alec C
authors: AC
authors: Kimmelman
authors: Ji-hye
authors: JH
authors: Paik
authors: Carol
authors: C
authors: Lim
authors: Samuel R
authors: SR
authors: Perry
authors: Shan
authors: S
authors: Jiang
authors: Brian
authors: B
authors: Malinn
authors: Alexei
authors: A
authors: Protopopov
authors: Simona
authors: S
authors: Colla
authors: Yonghong
authors: Y
authors: Xiao
authors: Aram F
authors: AF
authors: Hezel
authors: Nabeel
authors: N
authors: Bardeesy
authors: Shannon J
authors: SJ
authors: Turley
authors: Y Alan
authors: YA
authors: Wang
authors: Lynda
authors: L
authors: Chin
authors: Sarah P
authors: SP
authors: Thayer
authors: Ronald A
authors: RA
authors: DePinho
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D016207:Cytokines; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D016283:Proto-Oncogene Proteins p21(ras); C494929:PTEN protein, human; C487757:Pten protein, mouse; C495971:Hras protein, mouse