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A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma.
Lytle, Nikki K; Ferguson, L Paige; Rajbhandari, Nirakar; Gilroy, Kathryn; Fox, Raymond G; Deshpande, Anagha; Schürch, Christian M; Hamilton, Michael; Robertson, Neil; Lin, Wei; Noel, Pawan; Wartenberg, Martin; Zlobec, Inti; Eichmann, Micha; Galván, José A; Karamitopoulou, Eva; Gilderman, Tami; Esparza, Lourdes Adriana; Shima, Yutaka; Spahn, Philipp; French, Randall; Lewis, Nathan E; Fisch, Kathleen M; Sasik, Roman; Rosenthal, Sara Brin; Kritzik, Marcie; Von Hoff, Daniel; Han, Haiyong; Ideker, Trey; Deshpande, Aniruddha J; Lowy, Andrew M; Adams, Peter D; Reya, Tannishtha.
Afiliação
  • Lytle NK; Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
  • Ferguson LP; Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
  • Rajbhandari N; Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
  • Gilroy K; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK.
  • Fox RG; Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
  • Deshpande A; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • Schürch CM; Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, USA.
  • Hamilton M; Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
  • Robertson N; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK.
  • Lin W; Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
  • Noel P; Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
  • Wartenberg M; Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.
  • Zlobec I; Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.
  • Eichmann M; Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.
  • Galván JA; Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.
  • Karamitopoulou E; Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.
  • Gilderman T; Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
  • Esparza LA; Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
  • Shima Y; Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
  • Spahn P; Department of Pediatrics and the Novo Nordisk Foundation Center for Biosustainability, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • French R; Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • Lewis NE; Department of Pediatrics and the Novo Nordisk Foundation Center for Biosustainability, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • Fisch KM; Center for Computational Biology and Bioinformatics, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • Sasik R; Center for Computational Biology and Bioinformatics, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • Rosenthal SB; Center for Computational Biology and Bioinformatics, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • Kritzik M; Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
  • Von Hoff D; Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
  • Han H; Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
  • Ideker T; Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA; Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • Deshpande AJ; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • Lowy AM; Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA; Division of Surgical Oncology, Department of Surgery, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • Adams PD; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • Reya T; Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA; Department of Medicine, University
Cell ; 177(3): 572-586.e22, 2019 04 18.
Article em En | MEDLINE | ID: mdl-30955884
ABSTRACT
Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Células-Tronco Neoplásicas / Adenocarcinoma Idioma: En Revista: Cell Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Células-Tronco Neoplásicas / Adenocarcinoma Idioma: En Revista: Cell Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos