Development and cancer: at the crossroads of Nodal and Notch signaling

Abstract

Aggressive tumor cells express a plastic, multipotent phenotype similar to embryonic stem cells. However, the absence of major regulatory checkpoints in these tumor cells allows aberrant activation of embryonic signaling pathways, which seems to contribute to their plastic phenotype. Emerging evidence showing the molecular cross-talk between two major stem cell signaling pathways Nodal and Notch suggests a promising therapeutic strategy that could target aggressive tumor cells on the basis of their unique plasticity, and provide new insights into the mechanisms underlying the re-emergence of developmental signaling pathways during tumor progression.

Figure 1. Convergence of Nodal and Notch signaling

(A) Nodal can bind to ALK4/7 and ActRIIB receptors and induce smad-2/3/4-dependent signaling in a Cripto-1 dependent or independent manner, leading to activation of target genes including FoxH1, Nodal and Lefty. Binding of Notch receptors to ligands expressed on adjacent cells leads to enzymatic cleavage by gamma-secretase (γ-SC) and intracytoplasmic release of the active Notch intracellular domain (NICD). The CSL DNA binding protein can function as a transcriptional repressor. However, when NCID binds to CSL it forms an activator complex leading to target gene transcription. Cripto-1 may also play a role in regulating Notch expression in melanoma cells (broken arrows). (B) During the establishment of left-right asymmetry in mouse, Nodal expression around the node (ND) is directly regulated by Notch/Delta-like-1 (DLL1) signaling. This domain of Nodal expression is required for the subsequent expression of Nodal in the left lateral plate mesoderm (LLPM) which autoregulates its own expression, as well as the expression of Lefty2 in the LLPM and Lefty1 in the left presumptive floor plate. Together these proteins function to restrict Nodal signaling to the left side of the embryo where it induces left-sided structures. The Nodal coreceptor, CFC1 (Cryptic), an ortholog of human Cripto-1, is symmetrically expressed in both the left and right lateral plate mesoderm (RLPM), as well as in the node and along the left midline. Thin arrows indicate regulation at the transcriptional level. Block symbols indicate regulation at the protein level. Abbreviations: ND, node; NT, notochord, PS, primitive streak; LLPM, left lateral plate mesoderm; RLPM, right lateral plate mesoderm. (C) Human embryonic stem cell conditioned matrix (hESCMTX) contains factors, such as Lefty, capable of repressing Nodal expression in aggressive human melanoma cells (C8161). These cells also show increased miR-302a levels that could inhibit Notch signaling and Nodal expression. Inhibition of Nodal signaling may lead to redifferentiation or apoptosis in C8161 cells.