title: Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells.
abstract: Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.
authors.affiliation: Oncology Research Unit, Pfizer Inc., Pearl River, New York, USA. marc.damelin@pfizer.com
authors.forename: Marc
authors.initials: M
authors.lastname: Damelin
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Geles
authors.forename: Maximillian T
authors.initials: MT
authors.lastname: Follettie
authors.forename: Ping
authors.initials: P
authors.lastname: Yuan
authors.forename: Michelle
authors.initials: M
authors.lastname: Baxter
authors.forename: Jonathon
authors.initials: J
authors.lastname: Golas
authors.forename: John F
authors.initials: JF
authors.lastname: DiJoseph
authors.forename: Maha
authors.initials: M
authors.lastname: Karnoub
authors.forename: Shuguang
authors.initials: S
authors.lastname: Huang
authors.forename: Veronica
authors.initials: V
authors.lastname: Diesl
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.forename: Sung E
authors.initials: SE
authors.lastname: Choe
authors.forename: Carol
authors.initials: C
authors.lastname: Rios
authors.forename: Janet
authors.initials: J
authors.lastname: Gruzas
authors.forename: Latha
authors.initials: L
authors.lastname: Sridharan
authors.forename: Maureen
authors.initials: M
authors.lastname: Dougher
authors.forename: Arthur
authors.initials: A
authors.lastname: Kunz
authors.forename: Philip R
authors.initials: PR
authors.lastname: Hamann
authors.forename: Deborah
authors.initials: D
authors.lastname: Evans
authors.forename: Douglas
authors.initials: D
authors.lastname: Armellino
authors.forename: Kiran
authors.initials: K
authors.lastname: Khandke
authors.forename: Kimberly
authors.initials: K
authors.lastname: Marquette
authors.forename: Lioudmila
authors.initials: L
authors.lastname: Tchistiakova
authors.forename: Erwin R
authors.initials: ER
authors.lastname: Boghaert
authors.forename: Robert T
authors.initials: RT
authors.lastname: Abraham
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Bin-Bing S
authors.initials: BB
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis*; D051927:CD24 Antigen / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D000922:Immunotoxins / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000502:physiology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D000922:Immunotoxins; D008562:Membrane Glycoproteins; C031192:oncofetal antigens; C063709:trophoblastic glycoprotein 5T4, human