American Association for Cancer Research
00085472can190145-sup-215257_4_supp_5739932_pwy6vn.pdf (965.69 kB)

Supplementary Data from Kras/ADAM17-Dependent Jag1-ICD Reverse Signaling Sustains Colorectal Cancer Progression and Chemoresistance

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journal contribution
posted on 2023-03-31, 03:47 authored by Maria Pelullo, Francesca Nardozza, Sabrina Zema, Roberta Quaranta, Carmine Nicoletti, Zein Mersini Besharat, Maria Pia Felli, Bruna Cerbelli, Giulia d'Amati, Rocco Palermo, Carlo Capalbo, Claudio Talora, Lucia Di Marcotullio, Giuseppe Giannini, Saula Checquolo, Isabella Screpanti, Diana Bellavia

The supplementary material file contains additional data that sustain the oncogenic role of Jag1-ICD and information about reagents utilized, as follows: - Supplementary Figure S1 recapitulates the main gene mutations in CRC cell lines . - Supplementary Figures S2 and S3 show additional data supporting the role of Jag1-ICD in sustaining EMT and chemoresistance of CRC, respectively. - Supplementary Tables add information concerning reagents utilized. Table S1 reports the oligonucleotide primers; Table S2 reports the names and the source of the antibodies.





Colorectal cancer is characterized by well-known genetic defects and approximately 50% of cases harbor oncogenic Ras mutations. Increased expression of Notch ligand Jagged1 occurs in several human malignancies, including colorectal cancer, and correlates with cancer progression, poor prognosis, and recurrence. Herein, we demonstrated that Jagged1 was constitutively processed in colorectal cancer tumors with mutant Kras, which ultimately triggered intrinsic reverse signaling via its nuclear-targeted intracellular domain Jag1-ICD. This process occurred when Kras/Erk/ADAM17 signaling was switched on, demonstrating that Jagged1 is a novel target of the Kras signaling pathway. Notably, Jag1-ICD promoted tumor growth and epithelial–mesenchymal transition, enhancing colorectal cancer progression and chemoresistance both in vitro and in vivo. These data highlight a novel role for Jagged1 in colorectal cancer tumor 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 tumor pathogenesis and to confer chemoresistance through a noncanonical mechanism. These findings present a novel role of the transcriptionally active Jag1-ICD fragment to confer and mediate some of the activity of oncogenic KRAS.