Lateral inhibition of Notch signaling in neoplastic cells

// Kah Jing Lim 1, * , William D. Brandt 1, * , Jason A. Heth 4 , Karin M. Muraszko 4 , Xing Fan 4, 5 , Eli E. Bar 1, 6 , Charles G. Eberhart 1, 2, 3 1 Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, Maryland, USA 2 Department of Oncology, Johns Hopkins University, Baltimore, MD 21231, Maryland, USA 3 Department of Ophthalmology, Johns Hopkins University, Baltimore, MD 21231, Maryland, USA 4 Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, Michigan, USA 5 Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, Michigan, USA 6 Department of Neurological Surgery, Case Western University, Cleveland, OH 44106, Ohio, USA * These authors have contributed equally to this work Correspondence to: Charles G. Eberhart, e-mail: ceberha@jhmi.edu Keywords: Notch, lateral inhibition, cancer, signaling Received: October 24, 2014      Accepted: November 17, 2014      Published: February 13, 2015 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.