title: Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice.
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 Pparγ, the master regulator of adipocyte homeostasis. Accordingly, synthetic Pparγ 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.
authors: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 pbi@purdue.edu skuang@purdue.edu.
authors: Pengpeng
authors: 0000-0002-1955-7672
authors: P
authors: Bi
authors: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907.
authors: Feng
authors: F
authors: Yue
authors: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907.
authors: Anju
authors: A
authors: Karki
authors: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907.
authors: Beatriz
authors: B
authors: Castro
authors: School of Health Sciences, Purdue University, West Lafayette, IN 47907.
authors: Sara E
authors: SE
authors: Wirbisky
authors: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907.
authors: Chao
authors: 0000-0002-4051-364X
authors: C
authors: Wang
authors: Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907.
authors: Abigail
authors: 0000-0003-2262-8168
authors: A
authors: Durkes
authors: Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907 Center for Cancer Research, Purdue University, West Lafayette, IN 47907.
authors: Bennett D
authors: 0000-0002-6658-7970
authors: BD
authors: Elzey
authors: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907 Center for Cancer Research, Purdue University, West Lafayette, IN 47907.
authors: Ourania M
authors: 0000-0002-6230-0303
authors: OM
authors: Andrisani
authors: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907.
authors: Christopher A
authors: CA
authors: Bidwell
authors: School of Health Sciences, Purdue University, West Lafayette, IN 47907 Center for Cancer Research, Purdue University, West Lafayette, IN 47907.
authors: Jennifer L
authors: JL
authors: Freeman
authors: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907 Center for Cancer Research, Purdue University, West Lafayette, IN 47907.
authors: Stephen F
authors: 0000-0002-3281-3714
authors: SF
authors: Konieczny
authors: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 Center for Cancer Research, Purdue University, West Lafayette, IN 47907 pbi@purdue.edu skuang@purdue.edu.
authors: Shihuan
authors: 0000-0001-9180-3180
authors: S
authors: Kuang
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D054337:Cell Dedifferentiation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology; D003959:Diamines / Q000494:pharmacology; D003984:Dibenzazepines / Q000494:pharmacology; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects; D008080:Liposarcoma / Q000150:complications / Q000235:genetics / Q000473:pathology; D024821:Metabolic Syndrome / Q000473:pathology; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011230:Precancerous Conditions / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C000612000:24-diamino-5-phenylthiazole; D014408:Biomarkers, Tumor; D003959:Diamines; D003984:Dibenzazepines; D008024:Ligands; D047495:PPAR gamma; D051880:Receptors, Notch; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D051059:PTEN Phosphohydrolase; C527817:dibenzazepine