Cell, 2014-07, Vol.158 (1), p.185-197
- Kapoor, Avnish
- Yao, Wantong
- Ying, Haoqiang
- Hua, Sujun
- Liewen, Alison
- Wang, Qiuyun
- Zhong, Yi
- Wu, Chang-Jiun
- Sadanandam, Anguraj
- Hu, Baoli
- Chang, Qing
- Chu, Gerald C.
- Al-Khalil, Ramsey
- Jiang, Shan
- Xia, Hongai
- Fletcher-Sananikone, Eliot
- Lim, Carol
- Horwitz, Gillian I.
- Viale, Andrea
- Pettazzoni, Piergiorgio
- Sanchez, Nora
- Wang, Huamin
- Protopopov, Alexei
- Zhang, Jianhua
- Heffernan, Timothy
- Johnson, Randy L.
- Chin, Lynda
- Wang, Y. Alan
- Draetta, Giulio
- DePinho, Ronald A.
2014
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- Autor(en) / Beteiligte
- Kapoor, Avnish
- Yao, Wantong
- Ying, Haoqiang
- Hua, Sujun
- Liewen, Alison
- Wang, Qiuyun
- Zhong, Yi
- Wu, Chang-Jiun
- Sadanandam, Anguraj
- Hu, Baoli
- Chang, Qing
- Chu, Gerald C.
- Al-Khalil, Ramsey
- Jiang, Shan
- Xia, Hongai
- Fletcher-Sananikone, Eliot
- Lim, Carol
- Horwitz, Gillian I.
- Viale, Andrea
- Pettazzoni, Piergiorgio
- Sanchez, Nora
- Wang, Huamin
- Protopopov, Alexei
- Zhang, Jianhua
- Heffernan, Timothy
- Johnson, Randy L.
- Chin, Lynda
- Wang, Y. Alan
- Draetta, Giulio
- DePinho, Ronald A.
- Titel
- Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer
- Ist Teil von
- Cell, 2014-07, Vol.158 (1), p.185-197
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2014
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of KrasG12D–independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12D-independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC. [Display omitted] •Spontaneous tumor recurs following oncogenic Kras extinction-induced tumor regression•Yap1 amplification drives Kras-independent tumor relapse in Tead2-dependent manner•Yap1/Tead2 cooperate with E2F in promoting a cell-cycle gene expression program•Most Kras-independent tumors resemble the quasimesenchymal subtype of human PDAC In a mouse model of pancreatic cancer, amplification of Yap1 allows tumor cells to escape addiction to oncogenic Kras
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0092-8674eISSN: 1097-4172DOI: 10.1016/j.cell.2014.06.003Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4109295
- Format
- –
- Schlagworte
- Adaptor Proteins, Signal Transducing - metabolism, Adenocarcinoma - metabolism, Adenocarcinoma - pathology, Animals, Carcinoma, Pancreatic Ductal - metabolism, Carcinoma, Pancreatic Ductal - pathology, Cell Cycle, Cell Cycle Proteins, Cell Line, Tumor, Disease Models, Animal, DNA Replication, DNA-Binding Proteins - metabolism, E2F Transcription Factors - metabolism, Humans, Mice, Pancreatic Neoplasms - metabolism, Pancreatic Neoplasms - pathology, Phosphoproteins - metabolism, Proto-Oncogene Proteins - metabolism, Proto-Oncogene Proteins p21(ras) - metabolism, ras Proteins - metabolism, Transcription Factors - metabolism