Juxtacrine-mediated senescence induction. NOTCH ligands, such as JAG1 (J), associate with NOTCH receptors (N), which then undergo a series of proteolytic cleavage events. The resulting active form of NOTCH, the intracellular domain (ICD), is trans-located to the nucleus and induces NOTCH responsive genes. NIS cells (signal-sending cells) can upregulate JAG1 and transfer NOTCH signaling to adjacent normal cells (signal-receiving cells), thereby transferring the NIS phenotype to those signal-receiving cells (secondary NIS cells) through lateral induction. JAG1-expressing cancer cells can also be signal-sending cells in this context. NIS cells secrete distinct factors, which modulate the tissue microenvironment and may also impact signal-sending cancer cells.