title: Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT.
abstract: Metastasis frequently develops years after the removal of a primary tumor, from a minority of disseminated cancer cells that survived as latent entities through unknown mechanisms. We isolated latency competent cancer (LCC) cells from early stage human lung and breast carcinoma cell lines and defined the mechanisms that suppress outgrowth, support long-term survival, and maintain tumor-initiating potential in these cells during the latent metastasis stage. LCC cells show stem-cell-like characteristics and express SOX2 and SOX9 transcription factors, which are essential for their survival in host organs under immune surveillance and for metastatic outgrowth under permissive conditions. Through expression of the WNT inhibitor DKK1, LCC cells self-impose a slow-cycling state with broad downregulation of ULBP ligands for NK cells and evasion of NK-cell-mediated clearance. By expressing a Sox-dependent stem-like state and actively silencing WNT signaling, LCC cells can enter quiescence and evade innate immunity to remain latent for extended periods.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Malladi
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Danilo G
authors.initials: DG
authors.lastname: Macalinao
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: He
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Harihar
authors.initials: H
authors.lastname: Basnet
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: j-massague@ski.mskcc.org.
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007157:Immunologic Surveillance; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000276:immunology* / Q000473:pathology*; D055758:SOX9 Transcription Factor / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D019139:Tumor Escape; D060449:Wnt Signaling Pathway
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C527782:SOX2 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D055748:SOXB1 Transcription Factors