Kras/ADAM17-dependent Jag1-ICD reverse signalling sustains colorectal cancer progression and chemoresistance.

Colorectal cancer (CRC) is characterized by well-known genetic defects and approximately 50% of cases harbour oncogenic RAS mutations. Increased expression of Notch ligand Jagged1 occurs in several human malignancies, including CRC, and correlates with cancer progression, poor prognosis and recurrence. Herein, we demonstrated that Jagged1 was constitutively processed in CRC tumours with mutant Kras, which ultimately triggered intrinsic reverse signalling via its nuclear-targeted intracellular domain Jag1-ICD. This process occured when Kras/Erk/ADAM17 signalling was switched on, demonstrating that Jagged1 is a novel target of the Kras signalling pathway. Notably, Jag1-ICD promoted tumour growth and epithelial-mesenchymal transition, enhancing CRC progression and chemoresistance both in vitro and in vivo. These data highlight a novel role for Jagged1 in CRC tumour biology that may go beyond its effect on canonical Notch activation and suggest that Jag1-ICD may behave as an oncogenic driver that is able to sustain tumour pathogenesis and to confer chemoresistance through a non-canonical mechanism.