MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype.

Autor:	Sodir NM; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Kortlever RM; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Barthet VJA; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Campos T; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Pellegrinet L; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Kupczak S; Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom., Anastasiou P; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Swigart LB; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California., Soucek L; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Arends MJ; Division of Pathology, Cancer Research UK Edinburgh Centre, University of Edinburgh, Edinburgh, Scotland, United Kingdom., Littlewood TD; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Evan GI; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom. gie20@cam.ac.uk.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2020 Apr; Vol. 10 (4), pp. 588-607. Date of Electronic Publication: 2020 Jan 15.
DOI:	10.1158/2159-8290.CD-19-0435
Abstrakt:	The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of Myc in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells in vivo is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this Myc -driven PDAC switch is completely and immediately reversible: Myc deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible Myc switch. SIGNIFICANCE: We show that Myc activation in indolent Kras G12D -induced PanIN epithelium acts as an immediate pleiotropic switch, triggering tissue-specific signals that instruct all the diverse signature stromal features of spontaneous human PDAC. Subsequent Myc deactivation or inhibition immediately triggers a program that coordinately disassembles PDAC back to PanIN. See related commentary by English and Sears, p. 495 . (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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