title: Regulation of lung cancer metastasis by Klf4-Numb-like signaling.
abstract: Metastatic traits seem to be acquired by transformed cells with progenitor-like cancer-initiating properties, but there remains little mechanistic insight into this linkage. In this report, we show that the polarity protein Numbl, which is expressed normally in neuronal progenitors, becomes overexpressed and mislocalized in cancer cells from a variety of human tumors. Numbl overexpression relies on loss of the tumor suppressor miRNA-296-5p (miR-296), which actively represses translation of Numbl in normal cells. In turn, deregulated expression of Numbl mediates random tumor cell migration and invasion, blocking anoikis and promoting metastatic dissemination. In clinical specimens of non-small cell lung cancer, we found that Numbl overexpression correlated with a reduction in overall patient survival. Mechanistically, Numbl-mediated tumorigenesis involved suppression of a "stemness" transcriptional program driven by the stem cell programming transcription factor Klf4, thereby preserving a pool of progenitor-like cells in lung cancer. Our results reveal that Numbl-Klf4 signaling is critical to maintain multiple nodes of metastatic progression, including persistence of cancer-initiating cells, rationalizing its therapeutic exploitation to improve the treatment of advanced lung cancer.
authors: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors: Valentina
authors: V
authors: Vaira
authors: Alice
authors: A
authors: Faversani
authors: Nina M
authors: NM
authors: Martin
authors: David S
authors: DS
authors: Garlick
authors: Stefano
authors: S
authors: Ferrero
authors: Mario
authors: M
authors: Nosotti
authors: Joseph L
authors: JL
authors: Kissil
authors: Silvano
authors: S
authors: Bosari
authors: Dario C
authors: DC
authors: Altieri
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D016000:Cluster Analysis; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C549871:MIRN296 microRNA, human; D035683:MicroRNAs; C530266:NUMBL protein, human