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Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2016 Sep 19; Vol. 213 (10), pp. 2019-37. Date of Electronic Publication: 2016 Aug 29. - Publication Year :
- 2016
-
Abstract
- Liposarcomas (LPSs) are the most common soft-tissue cancer. Because of the lack of animal models, the cellular origin and molecular regulation of LPS remain unclear. Here, we report that mice with adipocyte-specific activation of Notch signaling (Ad/N1ICD) develop LPS with complete penetrance. Lineage tracing confirms the adipocyte origin of Ad/N1ICD LPS. The Ad/N1ICD LPS resembles human dedifferentiated LPS in histological appearance, anatomical localization, and gene expression signature. Before transformation, Ad/N1ICD adipocytes undergo dedifferentiation that leads to lipodystrophy and metabolic dysfunction. Although concomitant Pten deletion normalizes the glucose metabolism of Ad/N1ICD mice, it dramatically accelerates the LPS prognosis and malignancy. Transcriptomes and lipidomics analyses indicate that Notch activation suppresses lipid metabolism pathways that supply ligands to PparĪ³, the master regulator of adipocyte homeostasis. Accordingly, synthetic PparĪ³ ligand supplementation induces redifferentiation of Ad/N1ICD adipocytes and tumor cells, and prevents LPS development in Ad/N1ICD mice. Importantly, the Notch target HES1 is abundantly expressed in human LPS, and Notch inhibition suppresses the growth of human dedifferentiated LPS xenografts. Collectively, ectopic Notch activation is sufficient to induce dedifferentiation and tumorigenic transformation of mature adipocytes in mouse.<br /> (© 2016 Bi et al.)
- Subjects :
- Adipocytes drug effects
Animals
Biomarkers, Tumor metabolism
Cell Dedifferentiation drug effects
Cell Lineage drug effects
Cell Proliferation drug effects
Cell Transformation, Neoplastic genetics
Diabetes Mellitus, Experimental complications
Diabetes Mellitus, Experimental pathology
Diamines pharmacology
Dibenzazepines pharmacology
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation, Neoplastic drug effects
Humans
Ligands
Lipid Metabolism drug effects
Liposarcoma complications
Liposarcoma genetics
Liposarcoma pathology
Metabolic Syndrome pathology
Mice, Inbred C57BL
PPAR gamma metabolism
PTEN Phosphohydrolase metabolism
Precancerous Conditions pathology
Rosiglitazone
Signal Transduction drug effects
Thiazoles pharmacology
Thiazolidinediones pharmacology
Xenograft Model Antitumor Assays
Adipocytes metabolism
Adipocytes pathology
Cell Differentiation drug effects
Cell Differentiation genetics
Cell Transformation, Neoplastic metabolism
Cell Transformation, Neoplastic pathology
Receptors, Notch metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 213
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 27573812
- Full Text :
- https://doi.org/10.1084/jem.20160157