title: BRACHYURY confers cancer stem cell characteristics on colorectal cancer cells.
abstract: Cancer stem cells (CSCs) are initiating cells in colorectal cancer (CRC). Colorectal tumours undergo epithelial to mesenchymal transition (EMT)-like processes at the invasive front, enabling invasion and metastasis, and recent studies have linked this process to the acquisition of stem cell-like properties. It is of fundamental importance to understand the molecular events leading to the establishment of cancer initiating cells and how these mechanisms relate to cellular transitions during tumourigenesis. We use an in vitro system to recapitulate changes in CRC cells at the invasive front (mesenchymal-like cells) and central mass (epithelial-like cells) of tumours. We show that the mesoderm inducer BRACHYURY is expressed in a subpopulation of CRC cells that resemble invasive front mesenchymal-like cells, where it acts to impose characteristics of CSCs in a fully reversible manner, suggesting reversible formation and modulation of such cells. BRACHYURY, itself regulated by the oncogene β-catenin, influences NANOG and other 'stemness' markers including a panel of markers defining CRC-CSC whose presence has been linked to poor patient prognosis. Similar regulation of NANOG through BRACHYURY was observed in other cells lines, suggesting this might be a pathway common to cancer cells undergoing mesenchymal transition. We suggest that BRACHYURY may regulate NANOG in mesenchymal-like CRC cells to impose a 'plastic-state', allowing competence of cells to respond to signals prompting invasion or metastasis.
authors.affiliation: North West Cancer Research Fund Institute, School of Biological Sciences, Bangor University, Bangor, Gwynedd, United Kingdom.
authors.forename: Debalina
authors.initials: D
authors.lastname: Sarkar
authors.forename: Brian
authors.initials: B
authors.lastname: Shields
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Davies
authors.forename: Jürgen
authors.initials: J
authors.lastname: Müller
authors.forename: Jane A
authors.initials: JA
authors.lastname: Wakeman
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D018236:Carcinoma, Embryonal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis / Q000235:genetics; D002452:Cell Count; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005326:Fetal Proteins / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D010455:Peptides / Q000235:genetics; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics*; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics; D000098908:Brachyury Protein; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D006023:Glycoproteins; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D000071317:Nanog Homeobox Protein; D010455:Peptides; D020825:T-Box Domain Proteins; D051176:beta Catenin; D000098908:Brachyury Protein; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C497483:CD44 protein, human; C495270:CTNNB1 protein, human; C486780:NANOG protein, human