title: Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative.
abstract: Epithelial-to-mesenchymal transition (EMT) is an important driver of tumor invasion and metastasis, which causes many cancer deaths. Cancer stem cells (CSC) that maintain and initiate tumors have also been implicated in invasion and metastasis, but whether EMT is an important contributor to CSC function is unclear. In this study, we investigated whether a population of CSCs that have undergone EMT (EMT CSCs) exists in squamous cell carcinoma (SCC). We also determined whether a separate population of CSCs that retain epithelial characteristics (non-EMT CSCs) is also present. Our studies revealed that self-renewing CSCs in SCC include two biologically-distinct phenotypes. One phenotype, termed CD44(high)ESA(high), was proliferative and retained epithelial characteristics (non-EMT CSCs), whereas the other phenotype, termed CD44(high)ESA(low), was migratory and had mesenchymal traits characteristic of EMT CSCs. We found that non-EMT and EMT CSCs could switch their epithelial or mesenchymal traits to reconstitute the cellular heterogeneity which was characteristic of CSCs. However, the ability of EMT CSCs to switch to non-EMT character was restricted to cells that were also ALDH1(+), implying that only ALDH1(+) EMT cells had the ability to seed a new epithelial tumor. Taken together, our findings highlight the identification of two distinct CSC phenotypes and suggest a need to define therapeutic targets that can eradicate both of these variants to achieve effective SCC treatment.
authors.affiliation: Blizard Institute of Cell and Molecular Science, Queen Mary University of London, UK. a.biddle@qmul.ac.uk
authors.forename: Adrian
authors.initials: A
authors.lastname: Biddle
authors.forename: Xiao
authors.initials: X
authors.lastname: Liang
authors.forename: Luke
authors.initials: L
authors.lastname: Gammon
authors.forename: Bilal
authors.initials: B
authors.lastname: Fazil
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Harper
authors.forename: Helena
authors.initials: H
authors.lastname: Emich
authors.forename: Daniela Elena
authors.initials: DE
authors.lastname: Costea
authors.forename: Ian C
authors.initials: IC
authors.lastname: Mackenzie
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000032:analysis; D002465:Cell Movement; D049109:Cell Proliferation; D002999:Clone Cells / Q000473:pathology / Q000637:transplantation; D000071858:Epithelial Cell Adhesion Molecule; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D007527:Isoenzymes / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009062:Mouth Neoplasms / Q000473:pathology; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000637:transplantation; D010641:Phenotype; D011230:Precancerous Conditions / Q000473:pathology; D050697:Retinal Dehydrogenase / Q000502:physiology; D012871:Skin Diseases / Q000473:pathology; D012878:Skin Neoplasms / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D000951:Antigens, Neoplasm; C497483:CD44 protein, human; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D009363:Neoplasm Proteins; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase