Adenomatous polyposis coli (APC) mutation is the hallmark of colorectal cancer (CRC), resulting in constitutive WNT activation. Despite decades of research, targeting WNT signaling in cancer remains challenging due to its on-target toxicity. We have previously shown that the deubiquitinating enzyme USP7 is a tumor-specific WNT activator in APC-truncated cells by deubiquitinating and stabilizing β-catenin, but its role in gut tumorigenesis is unknown. Here, we show in vivo that deletion of Usp7 in Apc-truncated mice inhibits crypt hyperproliferation and intestinal tumor development. Loss of Usp7 prolongs the survival of the sporadic intestinal tumor model. Genetic deletion, but not pharmacological inhibition, of Usp7 in Apc+/− intestine induces colitis and enteritis. USP7 inhibitor treatment suppresses growth of patient-derived cancer organoids carrying APC truncations in vitro and in xenografts. Our findings provide direct evidence that USP7 inhibition may offer a safe and efficacious tumor-specific therapy for both sporadic and germline APC-mutated CRC.

USP7 inactivation suppresses APC-mutant intestinal hyperproliferation and tumor development / L. Novellasdemunt, A. Kucharska, A. Baulies, C. Hutton, G. Vlachogiannis, D. Repana, A. Rowan, A. Suarez-Bonnet, F. Ciccarelli, N. Valeri, V.S.W. Li. - In: STEM CELL REPORTS. - ISSN 2213-6711. - 18:2(2023), pp. 570-584. [10.1016/j.stemcr.2022.12.013]

USP7 inactivation suppresses APC-mutant intestinal hyperproliferation and tumor development

F. Ciccarelli;
2023

Abstract

Adenomatous polyposis coli (APC) mutation is the hallmark of colorectal cancer (CRC), resulting in constitutive WNT activation. Despite decades of research, targeting WNT signaling in cancer remains challenging due to its on-target toxicity. We have previously shown that the deubiquitinating enzyme USP7 is a tumor-specific WNT activator in APC-truncated cells by deubiquitinating and stabilizing β-catenin, but its role in gut tumorigenesis is unknown. Here, we show in vivo that deletion of Usp7 in Apc-truncated mice inhibits crypt hyperproliferation and intestinal tumor development. Loss of Usp7 prolongs the survival of the sporadic intestinal tumor model. Genetic deletion, but not pharmacological inhibition, of Usp7 in Apc+/− intestine induces colitis and enteritis. USP7 inhibitor treatment suppresses growth of patient-derived cancer organoids carrying APC truncations in vitro and in xenografts. Our findings provide direct evidence that USP7 inhibition may offer a safe and efficacious tumor-specific therapy for both sporadic and germline APC-mutated CRC.
APC; colorectal cancer; LGR5 stem cell; USP7; Wnt signaling
Settore BIOS-08/A - Biologia molecolare
2023
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1125895
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