title: Molecular Profiling of Circulating Tumour Cells Identifies Notch1 as a Principal Regulator in Advanced Non-Small Cell Lung Cancer.
abstract: Knowledge on the molecular mechanisms underlying metastasis colonization in Non-Small Cell Lung Cancer (NSCLC) remains incomplete. A complete overview integrating driver mutations, primary tumour heterogeneity and overt metastasis lacks the dynamic contribution of disseminating metastatic cells due to the inaccessibility to the molecular profiling of Circulating Tumour Cells (CTCs). By combining immunoisolation and whole genome amplification, we performed a global gene expression analysis of EpCAM positive CTCs from advanced NSCLC patients. We identified an EpCAM+ CTC-specific expression profile in NSCLC patients mostly associated with cellular movement, cell adhesion and cell-to-cell signalling mediated by PI3K/AKT, ERK1/2 and NF-kB pathways. NOTCH1 emerged as a driver connecting active signalling pathways, with a reduced number of related candidate genes (NOTCH1, PTP4A3, LGALS3 and ITGB3) being further validated by RT-qPCR on an independent cohort of NSCLC patients. In addition, these markers demonstrated high prognostic value for Progression-Free Survival (PFS). In conclusion, molecular characterization of EpCAM+ CTCs from advanced NSCLC patients provided with highly specific biomarkers with potential applicability as a "liquid biopsy" for monitoring of NSCLC patients and confirmed NOTCH1 as a potential therapeutic target to block lung cancer dissemination.
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Mariscal
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Alonso-Nocelo
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.|Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Muinelo-Romay
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Barbazan
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Vieito
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.|Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Abalo
authors.affiliation: School of Mathematics, University of Santiago de Compostela (Campus Vida), C/Lope Gomez de Marzoa s/n 15782 Santiago de Compostela, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez-Tato
authors.affiliation: School of Mathematics, University of Santiago de Compostela (Campus Vida), C/Lope Gomez de Marzoa s/n 15782 Santiago de Compostela, Spain.
authors.forename: Casares de Cal
authors.initials: CC
authors.lastname: Maria de Los Angeles
authors.affiliation: Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela, Spain.
authors.forename: Tomas
authors.initials: T
authors.lastname: Garcia-Caballero
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.
authors.forename: Carmela
authors.initials: C
authors.lastname: Rodriguez
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Brozos
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Baron
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.|Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Lopez-Lopez
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Abal
mesh_terms: D000072283:A549 Cells; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D000071858:Epithelial Cell Adhesion Molecule / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009360:Neoplastic Cells, Circulating / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D000071858:Epithelial Cell Adhesion Molecule; D016328:NF-kappa B; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D051881:Receptor, Notch1; D019869:Phosphatidylinositol 3-Kinases