USP7 inactivation suppresses APC-mutant intestinal hyperproliferation and tumor development.
journal contributionposted on 2023-02-23, 13:55 authored by Laura Novellasdemunt, Anna Kucharska, Anna Baulies, Colin Hutton, Georgios Vlachogiannis, Dimitra Repana, Andrew Rowan, A Suárez-Bonnet, Francesca Ciccarelli, Nicola Valeri, Vivian SW Li
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.
Crick (Grant ID: CC2141, Grant title: Li CC2141) European Commission (Grant ID: 668294 - INTENS, Grant title: EC 668294 - INTENS) Crick (Grant ID: CC2041, Grant title: Swanton CC2041) Crick (Grant ID: CC1061, Grant title: STP Experimental Histopathology)
APCcolorectal cancerLGR5 stem cellUSP7Wnt signalingHumansMiceAnimalsColorectal NeoplasmsUbiquitin-Specific Peptidase 7Adenomatous Polyposis ColiCarcinogenesisCell Transformation, NeoplasticWnt Signaling Pathwaybeta CateninSwanton CC2041Ciccarelli - secLi, V CC2141HPBRF-ack0601 Biochemistry and Cell Biology1103 Clinical Sciences