Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer
Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the ra...
Gespeichert in:
Veröffentlicht in: | Cancer cell 2020-10, Vol.38 (4), p.567-583.e11 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate-limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by KrasG12D expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1, enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests that activation of transforming growth factor β signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients.
[Display omitted]
•Knockout of Nsdhl switches pancreatic carcinoma from glandular to basal•Statins or Nsdhl knockout activates SREBP1-dependent Tgfb1 expression and EMT•PDACs in patients receiving statins have enhanced mesenchymal features•LDL cholesterol in vitro or in patients antagonizes SREBP1 and autocrine TGF-β
Gabitova-Cornell et al. show that disruption of cholesterol biosynthesis by Nsdhl knockout or treatment with statins switches glandular pancreatic carcinomas to a basal subtype via activation of SREBP1, which induces Tgfb1 expression, autocrine TGF-β-SMAD2/3 signaling, and epithelial-mesenchymal transition. |
---|---|
ISSN: | 1535-6108 1878-3686 |
DOI: | 10.1016/j.ccell.2020.08.015 |