title: ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit.
abstract: The drug efflux transporter ABCB5 identifies cancer stem-like cells (CSC) in diverse human malignancies, where its expression is associated with clinical disease progression and tumor recurrence. ABCB5 confers therapeutic resistance, but other functions in tumorigenesis independent of drug efflux have not been described that might help explain why it is so broadly overexpressed in human cancer. Here we show that in melanoma-initiating cells, ABCB5 controls IL1β secretion, which serves to maintain slow cycling, chemoresistant cells through an IL1β/IL8/CXCR1 cytokine signaling circuit. This CSC maintenance circuit involved reciprocal paracrine interactions with ABCB5-negative cancer cell populations. ABCB5 blockade induced cellular differentiation, reversed resistance to multiple chemotherapeutic agents, and impaired tumor growth in vivo. Together, our results defined a novel function for ABCB5 in CSC maintenance and tumor growth.
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wilson
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Karim R
authors.initials: KR
authors.lastname: Saab
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schatton
authors.affiliation: Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Pablo
authors.initials: P
authors.lastname: Pütz
authors.affiliation: Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.affiliation: Department of Surgery, University of Würzburg, Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gasser
authors.affiliation: Department of Surgery, University of Würzburg, Würzburg, Germany.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Waaga-Gasser
authors.affiliation: Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts. Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Natasha Y
authors.initials: NY
authors.lastname: Frank
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. markus.frank@childrens.harvard.edu.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Frank
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D046228:Microarray Analysis; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D023062:Receptors, Interleukin-8A / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: C480744:ABCB5 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D053583:Interleukin-1beta; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A