title: Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma.
abstract: Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44(high)EpCAM(low/-) CD24(+) cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Biddle
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Gammon
authors.affiliation: The Gade Laboratory of Pathology, Department of Clinical Medicine, University of Bergen, Norway.
authors.forename: Xiao
authors.initials: X
authors.lastname: Liang
authors.affiliation: The Gade Laboratory of Pathology, Department of Clinical Medicine, University of Bergen, Norway.
authors.forename: Daniela Elena
authors.initials: DE
authors.lastname: Costea
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Mackenzie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D000071858:Epithelial Cell Adhesion Molecule / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D019284:Thapsigargin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051927:CD24 Antigen; D000071858:Epithelial Cell Adhesion Molecule; D018960:Hyaluronan Receptors; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D019284:Thapsigargin
keywords: CSC; Cancer; EMT; Plasticity; Resistance; Stem cell; Therapy