title: CD66+ cells in cervical precancers are partially differentiated progenitors with neoplastic traits.
abstract: Cervical cancers, a malignancy associated with oncogenic papilloma viruses, remain a major disease burden in the absence of effective implementation of preventive strategies. CD66(+) cells have previously been identified as a tumor-propagating subset in cervical cancers. We investigated the existence, differentiation state, and neoplastic potential of CD66(+) cells in a precancer cell line harboring HPV31b episomes. The gene expression profile of CD66(high) cells overlaps with differentiated keratinocytes, neoplastic mesenchymal transition, cells of the squamocolumnar junction, and cervical cancer cell line-derived spheroids. There is elevated expression of DNMT1, Notch1, and the viral gene product E1⁁E4 in CD66(high) cells. Thus, CD66(high) cells, in the absence of differentiating signals, express higher levels of key regulators of keratinocytes stemness, differentiation, and the viral life cycle, respectively. We also find a striking association of neoplastic traits, including migration, invasion, and colony formation, in soft agar with CD66(high) cells. These properties and a distinct G2-M-enriched cell-cycle profile are conserved in cells from cervical cancers. Principally, using a precancerous cell line, we propose that CD66(high) cells have an intermediate differentiation state, with a cellular milieu connected with both viral replication and neoplastic potential, and validate some key features in precancer lesions. Such pathophysiologically relevant systems for defining cellular changes in the early phases of the disease process provide both mechanistic insight and potential therapeutic strategies. Collectively, our data provide a rationale for exploring novel therapeutic targets in CD66(+) subsets during cancer progression.
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS-GKVK Campus, Bangalore, Karnataka, India.
authors.forename: Chitra
authors.initials: C
authors.lastname: Pattabiraman
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Shiyuan
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Vignesh K
authors.initials: VK
authors.lastname: Gunasekharan
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS-GKVK Campus, Bangalore, Karnataka, India.
authors.forename: Annapurna
authors.initials: A
authors.lastname: Pranatharthi
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS-GKVK Campus, Bangalore, Karnataka, India.
authors.forename: Jeevisha
authors.initials: J
authors.lastname: Bajaj
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS-GKVK Campus, Bangalore, Karnataka, India.
authors.forename: Sweta
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS-GKVK Campus, Bangalore, Karnataka, India.
authors.forename: H
authors.initials: H
authors.lastname: Krishnamurthy
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS-GKVK Campus, Bangalore, Karnataka, India.
authors.forename: Aswathy
authors.initials: A
authors.lastname: Ammothumkandy
authors.affiliation: Department of Radiotherapy, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, India.
authors.forename: Venkat G
authors.initials: VG
authors.lastname: Giri
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Laimonis A
authors.initials: LA
authors.lastname: Laimins
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS-GKVK Campus, Bangalore, Karnataka, India. skrishna@ncbs.res.in.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Krishna
mesh_terms: D015703:Antigens, CD / Q000032:analysis*; D015815:Cell Adhesion Molecules / Q000032:analysis*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000032:analysis; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000166:cytology*; D027383:Papillomaviridae / Q000235:genetics; D011230:Precancerous Conditions / Q000473:pathology* / Q000821:virology; D051881:Receptor, Notch1 / Q000032:analysis; D002583:Uterine Cervical Neoplasms / Q000473:pathology* / Q000821:virology
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; C081876:CKAP4 protein, human; D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human