title: Constitutive proteasomal degradation of TWIST-1 in epithelial-ovarian cancer stem cells impacts differentiation and metastatic potential.
abstract: Epithelial-mesenchymal transition (EMT) is a critical process for embryogenesis but is abnormally activated during cancer metastasis and recurrence. This process enables epithelial cancer cells to acquire mobility and traits associated with stemness. It is unknown whether epithelial stem cells or epithelial cancer stem cells are able to undergo EMT, and what molecular mechanism regulates this process in these specific cell types. We found that epithelial-ovarian cancer stem cells (EOC stem cells) are the source of metastatic progenitor cells through a differentiation process involving EMT and mesenchymal-epithelial transition (MET). We demonstrate both in vivo and in vitro the differentiation of EOC stem cells into mesenchymal spheroid-forming cells (MSFCs) and their capacity to initiate an active carcinomatosis. Furthermore, we demonstrate that human EOC stem cells injected intraperitoneally in mice are able to form ovarian tumors, suggesting that the EOC stem cells have the ability to 'home' to the ovaries and establish tumors. Most interestingly, we found that TWIST-1 is constitutively degraded in EOC stem cells, and that the acquisition of TWIST-1 requires additional signals that will trigger the differentiation process. These findings are relevant for understanding the differentiation and metastasis process in EOC stem cells.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: G
authors.initials: G
authors.lastname: Yin
authors.forename: A B
authors.initials: AB
authors.lastname: Alvero
authors.forename: V
authors.initials: V
authors.lastname: Craveiro
authors.forename: J C
authors.initials: JC
authors.lastname: Holmberg
authors.forename: H-H
authors.initials: HH
authors.lastname: Fu
authors.forename: M K
authors.initials: MK
authors.lastname: Montagna
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: I
authors.initials: I
authors.lastname: Chefetz-Menaker
authors.forename: S
authors.initials: S
authors.lastname: Nuti
authors.forename: M
authors.initials: M
authors.lastname: Rossi
authors.forename: D-A
authors.initials: DA
authors.lastname: Silasi
authors.forename: T
authors.initials: T
authors.lastname: Rutherford
authors.forename: G
authors.initials: G
authors.lastname: Mor
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000378:metabolism*
chemical_list: D018960:Hyaluronan Receptors; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D046988:Proteasome Endopeptidase Complex