A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma.

Adenocarcinoma / genetics Animals Cell Adhesion Molecules / genetics Cell Differentiation Epigenesis, Genetic Gene Library Humans Mice Mice, Knockout Mice, SCID Neoplastic Stem Cells / cytology Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors Pancreatic Neoplasms / genetics RNA Interference RNA, Small Interfering / metabolism Receptors, G-Protein-Coupled / antagonists & inhibitors Receptors, Interleukin-10 / antagonists & inhibitors T-Lymphocytes / cytology Transcriptome Tumor Cells, Cultured
Msi Musashi PDAC RORg cancer cancer stem cells cytokines immune pancreatic cancer stem cells

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
18 04 2019
Historique:
received: 30 08 2018
revised: 18 01 2019
accepted: 04 03 2019
pubmed: 9 4 2019
medline: 16 1 2020
entrez: 9 4 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cell.2019.03.010 PMID: 30955884 PMC: PMC6711371
pubmed: 30955884
pii: S0092-8674(19)30272-7
doi: 10.1016/j.cell.2019.03.010
pmc: PMC6711371
mid: NIHMS1523556
pii:
doi:

Substances chimiques

Cell Adhesion Molecules 0
Nuclear Receptor Subfamily 1, Group F, Member 3 0
RNA, Small Interfering 0
Receptors, G-Protein-Coupled 0
Receptors, Interleukin-10 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

572-586.e22

Subventions

Organisme : NCATS NIH HHS
ID : UL1 TR001442
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA169281
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA186043
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA155620
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA206416
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007752
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197699
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM119850
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL086344
Pays : United States
Organisme : Cancer Research UK
ID : C10652-A16566
Pays : United Kingdom

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2019 Elsevier Inc. All rights reserved.

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Auteurs

Nikki K 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.

L Paige 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.

Nirakar 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.

Kathryn Gilroy (K)

Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK.

Raymond G 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.

Anagha Deshpande (A)

Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Christian M Schürch (CM)

Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, USA.

Michael 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.

Neil Robertson (N)

Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK.

Wei Lin (W)

Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.

Pawan Noel (P)

Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.

Martin Wartenberg (M)

Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.

Inti Zlobec (I)

Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.

Micha Eichmann (M)

Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.

José A Galván (JA)

Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.

Eva Karamitopoulou (E)

Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.

Tami 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.

Lourdes Adriana 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.

Yutaka 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.

Philipp 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.

Randall French (R)

Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA.

Nathan E 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.

Kathleen M Fisch (KM)

Center for Computational Biology and Bioinformatics, University of California, San Diego School of Medicine, La Jolla, CA, USA.

Roman Sasik (R)

Center for Computational Biology and Bioinformatics, University of California, San Diego School of Medicine, La Jolla, CA, USA.

Sara Brin Rosenthal (SB)

Center for Computational Biology and Bioinformatics, University of California, San Diego School of Medicine, La Jolla, CA, USA.

Marcie 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.

Daniel Von Hoff (D)

Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.

Haiyong Han (H)

Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.

Trey 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.

Aniruddha J Deshpande (AJ)

Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Andrew M 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.

Peter D 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.

Tannishtha 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 of California, San Diego School of Medicine, La Jolla, CA, USA. Electronic address: treya@ucsd.edu.

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Classifications MeSH

Recherchemedicale.com › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Eucaryotes › Animaux › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Facteurs biologiques › Antigènes › Antigènes de surface › Molécules d'adhérence cellulaire › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Phénomènes physiologiques cellulaires › Différenciation cellulaire › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Phénomènes génétiques › Structures génétiques › Banque de gènes › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A Multiscale Map of the Stem Cell State in...
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Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souches mutantes de souris › Souris SCID › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Cellules › Cellules souches › Cellules souches tumorales › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Membre-3 du groupe F de la sous-famille-1 de récepteurs nucléaires › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Extinction de l'expression des gènes › Interférence par ARN › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › Petit ARN interférent › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs couplés aux protéines G › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs aux cytokines › Récepteurs aux interleukines › Récepteurs à l'interleukine-10 › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Phénomènes génétiques › Structures génétiques › Transcriptome › A Multiscale Map of the Stem Cell State in...
Recherchemedicale.com › Cellules › Cellules cultivées › Cellules cancéreuses en culture › A Multiscale Map of the Stem Cell State in...