APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally, with the majority of cases initiated by inactivation of the APC tumor suppressor. This results in the constitutive transcriptional activation of the canonical WNT signal transduction pathway effector beta-Catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM. Here, we show that NOTUM retains cell-autonomous tumor suppressive activity in APC-null adenomatous lesions despite constitutive beta-Catenin activation. Strikingly, we find that NOTUM becomes an obligate oncogene upon subsequent P53 inactivation during the adenoma-adenocarcinoma transition, and that these phenotypes are WNT-independent, resulting from differential activity of NOTUM upon its enzymatic targets Glypican 1 and 4 in early vs. late-stage disease, respectively. Ultimately, preclinical mouse models of CRC and human tumoroid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonization of distal organs. The finding that a single agent targeting an extracellular enzyme is effective in treating highly aggressive tumors make NOTUM a novel therapeutic vulnerability in advanced colorectal adenocarcinomas.

Immune landscape in APC and TP53 related tumor microenvironment in colon adenocarcinoma: A bioinformatic analysis

“…These findings are consistent with previous studies that have also reported frequent mutations in APC and TP53 in COAD [ 18 , 19 ].…”

USP10 drives cancer stemness and enables super-competitor signalling in Colorectal Cancer

“…This observation is further supported by the organoid transplant model presented. The observed phenotype is in line with previous reports that inhibition NOTUM in established or transplanted CRC tumours does suppress tumour progression 40 . Here, pharmacologic targeting of USP10 by small molecule inhibitors 61 could extend the spectrum of possible intervention and open new avenues for CRC therapy.…”

“…24 weeks post-transplant mice were sacri ced, and tissue samples analysed. Mice transplanted with non-targeting control shRNA developed a large tumour, in line with previous reports for this genotype [39][40][41] . Loss of Usp10, while resulting in tumour organoid engraftment, led to smaller lesions (Fig.…”

Organoids in gastrointestinal diseases: from bench to clinic

“…Distinct mutation profiles call for tailored treatments, while different subtypes within the same disease require diverse therapeutic approaches 131,187,188 . By combining disease staging and considering various stages and characteristics along with molecular classification, specific treatment strategies can be tested using orgnaoids models prior to clinical drug trials 163,189,190 …”

“…131,187,188 By combining disease staging and considering various stages and characteristics along with molecular classification, specific treatment strategies can be tested using orgnaoids models prior to clinical drug trials. 163,189,190 Drug resistance has always been a major challenge in tumor therapy. Organoids models play a pivotal role in elucidating the mechanisms underlying drug resistance.…”