title: Autonomous stimulation of cancer cell plasticity by the human NKG2D lymphocyte receptor coexpressed with its ligands on cancer cells.
abstract: The stimulatory NKG2D receptor on lymphocytes promotes tumor immune surveillance by targeting ligands selectively induced on cancer cells. Progressing tumors counteract by employing tactics to disable lymphocyte NKG2D. This negative dynamic is escalated as some human cancer cells co-opt expression of NKG2D, thereby complementing the presence of its ligands for autonomous stimulation of oncogenic signaling. Clinical association data imply relationships between cancer cell NKG2D and metastatic disease. Here we show that NKG2D promotes cancer cell plasticity by induction of phenotypic, molecular, and functional signatures diagnostic of the epithelial-mesenchymal transition, and of stem-like traits via induction of Sox9, a key transcriptional regulator of breast stem cell maintenance. These findings obtained with model breast tumor lines and xenotransplants were recapitulated by ex vivo cancer cells from primary invasive breast carcinomas. Thus, NKG2D may have the capacity to drive high malignancy traits underlying metastatic disease.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Cai
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Zhenpeng
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Reeves
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Caballero-Benitez
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Duran
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Delrow
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Porter
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Spies
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Veronika
authors.initials: V
authors.lastname: Groh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D008024:Ligands; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism
chemical_list: C120528:HCST protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt