Motility and stem cell properties induced by the epithelial-mesenchymal transition require destabilization of lipid rafts.
The Epithelial-Mesenchymal Transition (EMT) is a developmental program that provides cancer cells with the characteristics necessary for metastasis, including increased motility and stem cell properties. The cellular and molecular mechanisms underlying this process are not yet fully understood, hampering efforts to develop therapeutics. In recent years, it has become apparent that EMT is accompanied by wholesale changes in diverse signaling pathways that are initiated by proteins at the plasma membrane (PM). The PM contains thousands of lipid and protein species that are dynamically and spatially organized into lateral membrane domains, an example of which are lipid rafts. Since one of the major functions of rafts is modulation of signaling originating at the PM, we hypothesized that the signaling changes occurring during an EMT are associated with alterations in PM organization. To test this hypothesis, we used Giant Plasma Membrane Vesicles (GPMVs) to study the organization of intact plasma membranes isolated from live cells. We observed that induction of EMT significantly destabilized lipid raft domains. Further, this reduction in stability was crucial for the maintenance of the stem cell phenotype and EMT-induced remodeling of PM-orchestrated pathways. Exogenously increasing raft stability by feeding cells with ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) repressed these phenotypes without altering EMT markers, and inhibited the metastatic capacity of breast cancer cells. Hence, modulating raft properties regulates cell phenotype, suggesting a novel approach for targeting the impact of EMT in cancer.
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Michael J
MJ
Tisza
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Weina
W
Zhao
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Jessie S R
JS
Fuentes
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Sara
S
Prijic
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Xiaoling
X
Chen
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Ilya
I
Levental
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.|Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jeffrey T
JT
Chang
D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D002463:Cell Membrane Permeability; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
cell motility; epithelial-mesenchymal transition; lipid rafts; plasma membrane; stem cell properties