title: EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression.
abstract: Epithelial-to-mesenchymal transition (EMT) is associated with metastasis formation as well as with generation and maintenance of cancer stem cells. In this way, EMT contributes to tumor invasion, heterogeneity and chemoresistance. Morphological and functional changes involved in these processes require robust reprogramming of gene expression, which is only partially accomplished at the transcriptional level. Alternative splicing is another essential layer of gene expression regulation that expands the cell proteome. This step in post-transcriptional regulation of gene expression tightly controls cell identity between epithelial and mesenchymal states and during stem cell differentiation. Importantly, dysregulation of splicing factor function and cancer-specific splicing isoform expression frequently occurs in human tumors, suggesting the importance of alternative splicing regulation for cancer biology.In this review, we briefly discuss the role of EMT programs in development, stem cell differentiation and cancer progression. Next, we focus on selected examples of key factors involved in EMT and stem cell differentiation that are regulated post-transcriptionally through alternative splicing mechanisms. Lastly, we describe relevant oncogenic splice-variants that directly orchestrate cancer stem cell biology and tumor EMT, which may be envisioned as novel targets for therapeutic intervention.
authors.affiliation: Istituto di Genetica Molecolare - Consiglio Nazionale delle Ricerche, via Abbiategrasso 207, 27100, Pavia, Italy.|Dipartimento di Biologia e Biotecnologie, 'Lazzaro Spallanzani' - Universita` degli Studi di Pavia, via Ferrata 9, 27100, Pavia, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Pradella
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133, Rome, Italy.|Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Naro
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133, Rome, Italy. claudio.sette@uniroma2.it.|Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143, Rome, Italy. claudio.sette@uniroma2.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Sette
authors.affiliation: Istituto di Genetica Molecolare - Consiglio Nazionale delle Ricerche, via Abbiategrasso 207, 27100, Pavia, Italy. arneri@igm.cnr.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ghigna
mesh_terms: D017398:Alternative Splicing; D014408:Biomarkers, Tumor / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D014411:Neoplastic Stem Cells / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor
keywords: Alternative splicing; Cancer stem cells; EMT; RNA binding proteins; Stem cell differentiation; Tumor progression