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.

Fine-Tuning of the Kaposi’s Sarcoma-Associated Herpesvirus Life Cycle in Neighboring Cells through the RTA-JAG1-Notch Pathway

“…In addition to its involvement in the pathogenesis of diseases, Notch signaling plays a critical role in asymmetric cell division and fate determination, which is reflected by distinct gene expression among cells. In signal receiving cells, Notch is activated by the binding of Notch receptors to membrane-anchored Notch ligands on neighboring cells (signal donor cells) where Notch signaling is inhibited by the ligand intracellular domain and other regulatory factors [ 27 , 75 ], which is known as lateral inhibition. Our results suggest that asymmetric gene expression induced by lateral inhibition affects the behavior of KSHV in infected cells.…”

“…It enables short-range communication between the cells of metazoans through physical contact [ 21 ] and regulates many cellular functions including proliferation, death, and differentiation [ 21 – 24 ]. It is unique for its ability to specify the fate of the adjacent cells within an equivalence group into different (sometimes opposite) directions by cell-to-cell communication and subsequently altered gene expression, known as lateral inhibition [ 25 – 27 ]. Aberrant gain or loss of Notch function is linked to a wide range of human disorders, including developmental disorders and cancers [ 28 , 29 ].…”

Highly Tumorigenic Diffuse Large B Cell Lymphoma Cells Are Produced by Coculture with Stromal Cells

“…Adjacent homogeneous cells with different cell fates can be attributed to the differential activation of the Notch pathway, which has been well described in many physical conditions and developmental processes [52, 53]. Phenomena such as lateral inhibition, in which adjacent cells become signal-sending/receiving cells due to differential expression of Notch receptors or ligands, have been found in neoplasms in recent studies [54]. It can be inferred that Notch3-bearing cells send signals to adjacent tumor cells, which then become highly tumorigenic cancer stem-like cells.…”

Deregulation of the Notch pathway as a common road in viral carcinogenesis

“…C, Boundary formation: Boundaries are borders between 2 adjacent cell types that prevent them becoming mixed. NOTCH activity modulates microRNA expression thus contributing to formation of structures that define the boundary on, Ellisen et al 19 described the t (7,9) translocation which is common in T cell acute lymphoblastic leukemia (T-ALL). In fact, NOTCH1 mutations are frequently observed in the development of T-ALL, causing ligand-independent NOTCH1 activation and increased N1ICD stability.…”

“…The Notch signaling pathway has 3 main functions: lateral inhibition, asymmetric lineage decisions, and boundary formation (Figure ) . The NOTCH receptors (NOTCH1‐4) and the Delta, Serrata, and Lag2 (DSL) ligands, Jagged‐1 and 2 (JAG1‐2) and Delta‐like 1, 3, and 4 (DLL1‐3‐4) in mammals, are expressed at the cell membrane .…”