title: Paracrine signaling between tumor subclones of mouse SCLC: a critical role of ETS transcription factor Pea3 in facilitating metastasis.
abstract: Tumor heterogeneity can create a unique symbiotic tumor microenvironment. Earlier, we showed that clonal evolution in mouse small cell lung cancer (SCLC) can result in subclones that, upon cografting, endow the neuroendocrine tumor cells with metastatic potential. We now show that paracrine signaling between SCLC subclones is a critical requirement in the early steps of the metastatic process, such as local invasion and intravasation. We further show evidence that paracrine signaling via fibroblast growth factor 2 (Fgf2) and Mapk between these diverged tumor subclones causes enhanced expression of the Pea3 (polyomavirus enhancer activator 3) transcription factor, resulting in metastatic dissemination of the neuroendocrine tumor subclones. Our data reveal for the first time paracrine signaling between tumor cell subclones in SCLC that results in metastatic spread of SCLC.
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
authors.forename: Min-chul
authors.initials: MC
authors.lastname: Kwon
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
authors.forename: Natalie
authors.initials: N
authors.lastname: Proost
authors.affiliation: Department of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
authors.forename: Kate D
authors.initials: KD
authors.lastname: Sutherland
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
authors.forename: John
authors.initials: J
authors.lastname: Zevenhoven
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Skolkovo Institute of Science and Technology, Skolkovo Innovation Center, Moscow 143026, Russia.
authors.forename: Anton
authors.initials: A
authors.lastname: Berns
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics / Q000503:physiopathology*; D019899:Paracrine Communication / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000503:physiopathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; C065788:transcription factor PEA3; D016222:Fibroblast Growth Factor 2; D019950:Mitogen-Activated Protein Kinase 1
keywords: Fgf2; Pea3; metastasis; small cell lung cancer; tumor heterogeneity