NOTCH SIGNALING IN CONTEXT: BASIC AND TRANSLATIONAL IMPLICATIONS.

Notch receptors participate is a highly conserved signaling pathway that regulates numerous facets of cellular behavior, has protean roles during development and in adult tissue homeostasis, and is frequently dysregulated in human diseases, particularly cancer. These relationships to disease and the ability to modulate Notch signaling at multiple levels have engendered attempts to target Notch therapeutically, but incomplete understanding of the outcomes of Notch activation and on-target toxicity have stymied efforts to date. Using well-controlled experimental systems, we have pursued studies that seek to understand how Notch influences the behavior of different types of cancer cells. Our work suggests that Notch effects are defined by epigenetic landscapes that are "laid out" by upstream pioneer transcription factors, which act to delineate the outcome of Notch activation. These insights define some of the "rules" that govern Notch functions and constitute one step toward bringing safe and effective targeting of Notch to fruition.