title: Plasticity underlies tumor progression: role of Nodal signaling.
abstract: The transforming growth factor beta (TGFβ) superfamily member Nodal is an established regulator of early embryonic development, with primary roles in endoderm induction, left-right asymmetry, and primitive streak formation. Nodal signals through TGFβ family receptors at the plasma membrane and induces signaling cascades leading to diverse transcriptional regulation. While conceptually simple, the regulation of Nodal and its molecular effects are profoundly complex and context dependent. Pioneering work by developmental biologists has characterized the signaling pathways, regulatory components, and provided detailed insight into the mechanisms by which Nodal mediates changes at the cellular and organismal levels. Nodal is also an important factor in maintaining pluripotency of embryonic stem cells through regulation of core transcriptional programs. Collectively, this work has led to an appreciation for Nodal as a powerful morphogen capable of orchestrating multiple cellular phenotypes. Although Nodal is not active in most adult tissues, its reexpression and signaling have been linked to multiple types of human cancer, and Nodal has emerged as a driver of tumor growth and cellular plasticity. In vitro and in vivo experimental evidence has demonstrated that inhibition of Nodal signaling reduces cancer cell aggressive characteristics, while clinical data have established associations with Nodal expression and patient outcomes. As a result, there is great interest in the potential targeting of Nodal activity in a therapeutic setting for cancer patients that may provide new avenues for suppressing tumor growth and metastasis. In this review, we evaluate our current understanding of the complexities of Nodal function in cancer and highlight recent experimental evidence that sheds light on the therapeutic potential of its inhibition.
authors.affiliation: Stanley Manne Children's Research Institute, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 225 E. Chicago Avenue, Box 222, Chicago, IL, 60611, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bodenstine
authors.affiliation: Stanley Manne Children's Research Institute, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 225 E. Chicago Avenue, Box 222, Chicago, IL, 60611, USA.
authors.forename: Grace S
authors.initials: GS
authors.lastname: Chandler
authors.affiliation: Stanley Manne Children's Research Institute, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 225 E. Chicago Avenue, Box 222, Chicago, IL, 60611, USA.
authors.forename: Richard E B
authors.initials: RE
authors.lastname: Seftor
authors.affiliation: Stanley Manne Children's Research Institute, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 225 E. Chicago Avenue, Box 222, Chicago, IL, 60611, USA.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Seftor
authors.affiliation: Stanley Manne Children's Research Institute, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 225 E. Chicago Avenue, Box 222, Chicago, IL, 60611, USA. m-hendrix@northwestern.edu.
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
mesh_terms: D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D055457:Nodal Protein / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: C526007:NODAL protein, human; D055457:Nodal Protein; D016212:Transforming Growth Factor beta
keywords: Cancer stem cells; Embryogenesis; Nodal; Pluripotency