Colorectal cancer (CRC) is characterized by well-known genetic defects and about 50% of the 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 demonstrate that Jagged1 is constitutively processed in CRC tumours with mutant Kras, ultimately triggering an intrinsic reverse signalling via its nuclear-targeted intracellular domain (Jag1-ICD). We provide evidence that the processing occurs when a Kras/Erk/ADAM17 signalling axis is switched on, demonstrating that Jagged1 is a novel target of Kras signalling pathway. Notably, we show that Jag1-ICD promotes tumour growth and epithelial mesenchymal transition, enhancing CRC progression and chemoresistance both in vitro and in vivo. Our data pinpoint 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 a novel oncogenic driver, able to sustain tumour pathogenesis and to confer chemoresistance, through a non-canonical mechanism. By unveiling the Kras/Erk/ADAM17/Jagged1 signalling axis, we provide new mechanistic insights on CRC tumour biology and highlight a novel attractive target for CRC therapy.

Kras/ADAM17-dependent Jag1-ICD reverse signalling sustains CRC progression and chemoresistance / Pelullo, Maria; Nardozza, Francesca; Zema, Sabrina; Quaranta, Roberta; Nicoletti, Carmine; Besharat, Zein Mersini; Felli, Maria Pia; Cerbelli, Bruna; d’Amati, Giulia; Palermo, Rocco; Capalbo, Carlo; Talora, Claudio; Di Marcotullio, Lucia; Giannini, Giuseppe; Checquolo, Saula; Screpanti, Isabella; Bellavia, Diana. - In: CANCER RESEARCH. - ISSN 1538-7445. - 79:21(2019), pp. 5575-5586. [10.1158/0008-5472.CAN-19-0145]

Kras/ADAM17-dependent Jag1-ICD reverse signalling sustains CRC progression and chemoresistance

Pelullo Maria
Primo
;
Nardozza Francesca
Secondo
;
Zema Sabrina;Quaranta Roberta;Nicoletti Carmine;Zein Mersini Besharat;Felli Maria Pia;Cerbelli Bruna;d’Amati Giulia;Palermo Rocco;Capalbo Carlo;Talora Claudio;Di Marcotullio Lucia;Giannini Giuseppe;Checquolo Saula
;
Screpanti Isabella
Penultimo
;
Diana Bellavia
Ultimo
2019

Abstract

Colorectal cancer (CRC) is characterized by well-known genetic defects and about 50% of the 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 demonstrate that Jagged1 is constitutively processed in CRC tumours with mutant Kras, ultimately triggering an intrinsic reverse signalling via its nuclear-targeted intracellular domain (Jag1-ICD). We provide evidence that the processing occurs when a Kras/Erk/ADAM17 signalling axis is switched on, demonstrating that Jagged1 is a novel target of Kras signalling pathway. Notably, we show that Jag1-ICD promotes tumour growth and epithelial mesenchymal transition, enhancing CRC progression and chemoresistance both in vitro and in vivo. Our data pinpoint 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 a novel oncogenic driver, able to sustain tumour pathogenesis and to confer chemoresistance, through a non-canonical mechanism. By unveiling the Kras/Erk/ADAM17/Jagged1 signalling axis, we provide new mechanistic insights on CRC tumour biology and highlight a novel attractive target for CRC therapy.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1310873
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