CCN4 and neoplasm: Our study identified Notch1 signaling as a crucial molecular determinant in governing the tumor-regulating role of MSC-derived stromal fibroblasts and opens a new avenue to target the TME by either reprograming and converting CAF from ‘tumor promoters’ to ‘tumor suppressors’ through therapeutic activation of the Notch1 pathway or by directly exploiting Notch's downstream target, WISP-1.