The true functional consequences for each Notch mutation found in a patients’ tumor cells remain poorly understood and likely depend not only on the oncogenic nature, e.g., of a certain NOTCH1 point mutation, but also on the mutational context of the tumor and its remaining lineage-specific, in this case epithelial, differentiation potential, while not even speaking of the interaction with the TME and the ECM. Here, NOTCH1 is linked to neoplasm.