title: Lateral inhibition of Notch signaling in neoplastic cells.
abstract: During normal development, heterogeneous expression of Notch ligands can result in pathway suppression in the signal-sending cell, a process known as lateral inhibition. It is unclear if an analogous phenomenon occurs in malignant cells. We observed significant induction of Notch ligands in glioblastoma neurospheres and pancreatic carcinoma cells cultured in low oxygen, suggesting that this phenomenon could occur around hypoxic regions. To model lateral inhibition in these tumors, the ligand Jagged1 was overexpressed in glioblastoma and pancreatic carcinoma cells, resulting in overall induction of pathway targets. However, when ligand high and ligand low cells from a single line were co-cultured and then separated, we noted suppression of Notch pathway targets in the former and induction in the latter, suggesting that neoplastic lateral inhibition can occur. We also found that repression of Notch pathway targets in signal-sending cells may occur through the activity of a Notch ligand intracellular domain, which translocates into the nucleus. Understanding how this neoplastic lateral inhibition process functions in cancer cells may be important in targeting ligand driven Notch signaling in solid tumors.
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, Maryland, USA.
authors.forename: Kah Jing
authors.initials: KJ
authors.lastname: Lim
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, Maryland, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Brandt
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, Michigan, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Heth
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, Michigan, USA.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Muraszko
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, Michigan, USA.|Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, Michigan, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, Maryland, USA.|Department of Neurological Surgery, Case Western University, Cleveland, OH 44106, Ohio, USA.
authors.forename: Eli E
authors.initials: EE
authors.lastname: Bar
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, Maryland, USA.|Department of Oncology, Johns Hopkins University, Baltimore, MD 21231, Maryland, USA.|Department of Ophthalmology, Johns Hopkins University, Baltimore, MD 21231, Maryland, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
mesh_terms: D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C490504:JAG2 protein, human; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins