title: A rare population of CD24(+)ITGB4(+)Notch(hi) cells drives tumor propagation in NSCLC and requires Notch3 for self-renewal.
abstract: Sustained tumor progression has been attributed to a distinct population of tumor-propagating cells (TPCs). To identify TPCs relevant to lung cancer pathogenesis, we investigated functional heterogeneity in tumor cells isolated from Kras-driven mouse models of non-small-cell lung cancer (NSCLC). CD24(+)ITGB4(+)Notch(hi) cells are capable of propagating tumor growth in both a clonogenic and an orthotopic serial transplantation assay. While all four Notch receptors mark TPCs, Notch3 plays a nonredundant role in tumor cell propagation in two mouse models and in human NSCLC. The TPC population is enriched after chemotherapy, and the gene signature of mouse TPCs correlates with poor prognosis in human NSCLC. The role of Notch3 in tumor propagation may provide a therapeutic target for NSCLC.
authors.affiliation: Cancer Biology Program, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Cecile C
authors.initials: CC
authors.lastname: de la Cruz
authors.forename: Leanne C
authors.initials: LC
authors.lastname: Sayles
authors.forename: Chris
authors.initials: C
authors.lastname: Alleyne-Chin
authors.forename: Dedeepya
authors.initials: D
authors.lastname: Vaka
authors.forename: Tim D
authors.initials: TD
authors.lastname: Knaak
authors.forename: Marty
authors.initials: M
authors.lastname: Bigos
authors.forename: Yue
authors.initials: Y
authors.lastname: Xu
authors.forename: Chuong D
authors.initials: CD
authors.lastname: Hoang
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Shrager
authors.forename: Hans Joerg
authors.initials: HJ
authors.lastname: Fehling
authors.forename: Dorothy
authors.initials: D
authors.lastname: French
authors.forename: William
authors.initials: W
authors.lastname: Forrest
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Jiang
authors.forename: Richard A D
authors.initials: RA
authors.lastname: Carano
authors.forename: Kai H
authors.initials: KH
authors.lastname: Barck
authors.forename: Erica L
authors.initials: EL
authors.lastname: Jackson
authors.forename: E Alejandro
authors.initials: EA
authors.lastname: Sweet-Cordero
mesh_terms: D000818:Animals; D051927:CD24 Antigen / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology* / Q000473:pathology; D006801:Humans; D039663:Integrin beta4 / Q000032:analysis*; D008175:Lung Neoplasms / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000502:physiology*; D018874:Spheroids, Cellular
chemical_list: D051927:CD24 Antigen; C497889:CD24 protein, human; C059834:ITGB4 protein, human; D039663:Integrin beta4; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch