PMID- 26560028 OWN - NLM STAT- MEDLINE DCOM- 20151214 LR - 20240104 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 527 IP - 7579 DP - 2015 Nov 26 TI - Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. PG - 525-530 LID - 10.1038/nature16064 [doi] AB - Diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis despite current best therapies; therefore new treatment strategies are urgently required. Numerous studies have suggested that epithelial-to-mesenchymal transition (EMT) contributes to early-stage dissemination of cancer cells and is pivotal for invasion and metastasis of PDAC. EMT is associated with phenotypic conversion of epithelial cells into mesenchymal-like cells in cell culture conditions, although such defined mesenchymal conversion (with spindle-shaped morphology) of epithelial cells in vivo is rare, with quasi-mesenchymal phenotypes occasionally observed in the tumour (partial EMT). Most studies exploring the functional role of EMT in tumours have depended on cell-culture-induced loss-of-function and gain-of-function experiments involving EMT-inducing transcription factors such as Twist, Snail and Zeb1 (refs 2, 3, 7-10). Therefore, the functional contribution of EMT to invasion and metastasis remains unclear, and genetically engineered mouse models to address a causal connection are lacking. Here we functionally probe the role of EMT in PDAC by generating mouse models of PDAC with deletion of Snail or Twist, two key transcription factors responsible for EMT. EMT suppression in the primary tumour does not alter the emergence of invasive PDAC, systemic dissemination or metastasis. Suppression of EMT leads to an increase in cancer cell proliferation with enhanced expression of nucleoside transporters in tumours, contributing to enhanced sensitivity to gemcitabine treatment and increased overall survival of mice. Collectively, our study suggests that Snail- or Twist-induced EMT is not rate-limiting for invasion and metastasis, but highlights the importance of combining EMT inhibition with chemotherapy for the treatment of pancreatic cancer. FAU - Zheng, Xiaofeng AU - Zheng X AD - Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Carstens, Julienne L AU - Carstens JL AD - Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Kim, Jiha AU - Kim J AD - Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Scheible, Matthew AU - Scheible M AD - Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Kaye, Judith AU - Kaye J AD - Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Sugimoto, Hikaru AU - Sugimoto H AD - Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Wu, Chia-Chin AU - Wu CC AD - Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - LeBleu, Valerie S AU - LeBleu VS AD - Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Kalluri, Raghu AU - Kalluri R AD - Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. AD - Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. AD - Department of Bioengineering, Rice University, Houston, Texas. LA - eng SI - GEO/GSE66981 GR - P30CA16672/CA/NCI NIH HHS/United States GR - U54 CA163191/CA/NCI NIH HHS/United States GR - P30 CA016672/CA/NCI NIH HHS/United States GR - U01 CA151925/CA/NCI NIH HHS/United States GR - R01 CA125550/CA/NCI NIH HHS/United States GR - R01 CA155370/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151111 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Nucleoside Transport Proteins) RN - 0 (Snail Family Transcription Factors) RN - 0 (Transcription Factors) RN - 0 (Twist-Related Protein 1) RN - 0W860991D6 (Deoxycytidine) RN - 0 (Gemcitabine) SB - IM CIN - Nature. 2015 Nov 26;527(7579):452-3. PMID: 26560026 MH - Adenocarcinoma/drug therapy/metabolism/pathology MH - Animals MH - Carcinoma, Pancreatic Ductal/drug therapy/metabolism/pathology MH - Cell Proliferation/drug effects MH - Deoxycytidine/analogs & derivatives/pharmacology/therapeutic use MH - Disease Models, Animal MH - Disease Progression MH - Drug Resistance, Neoplasm/*drug effects MH - *Epithelial-Mesenchymal Transition MH - Female MH - Male MH - Mice MH - Neoplasm Invasiveness/pathology MH - Neoplasm Metastasis/*pathology MH - Nucleoside Transport Proteins/metabolism MH - Pancreatic Neoplasms/*drug therapy/genetics/metabolism/*pathology MH - Snail Family Transcription Factors MH - Survival Analysis MH - Transcription Factors/deficiency/genetics/metabolism MH - Twist-Related Protein 1/deficiency/genetics/metabolism MH - Gemcitabine PMC - PMC4849281 MID - NIHMS729654 EDAT- 2015/11/13 06:00 MHDA- 2015/12/15 06:00 PMCR- 2016/05/18 CRDT- 2015/11/13 06:00 PHST- 2015/06/10 00:00 [received] PHST- 2015/10/08 00:00 [accepted] PHST- 2015/11/13 06:00 [entrez] PHST- 2015/11/13 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] PHST- 2016/05/18 00:00 [pmc-release] AID - 10.1038/nature16064 [doi] PST - ppublish SO - Nature. 2015 Nov 26;527(7579):525-530. doi: 10.1038/nature16064. Epub 2015 Nov 11.