Maurice, M. | bioRxiv Science

bioRxiv2023

Stabilisation of β-Catenin-WNT signalling by USP10 in APC-truncated colorectal cancer drives cancer stemness and enables super-competitor signalling

The contribution of deubiquitylating enzymes to {beta}-Catenin stabilisation in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, we report the deubiquitylase USP10 as an APC-truncation- specific enhancer of {beta}-Catenin stability, potentiating WNT signalling in CRC and cancer stem cells. Mechanistically, interaction studies in various CRC cell lines and in vitro binding studies, together with computational modelling, revealed that USP10 binding to {beta}-Catenin is mediated via the unstructured N-terminus of USP10 and requires the absence of full-length APC. Notably, loss of USP10 in CRISPR engineered intestinal organoids reduces tumorigenic properties of CRC and blocks the super competitor-signalling of APC-mutated CRC. Furthermore, reduction of USP10 induces the expression of differentiation genes, and opposes the APC-truncated phenotype in an intestinal hyperplasia model of D.melanogaster. Taken together, our findings reveal USP10s role in intestinal tumourigenesis by stabilising {beta}-Catenin, leading to aberrant WNT signalling, enhancing cancer cell stemness and implicate the DUB USP10 as a cancer specific therapeutic vulnerability in Apc truncated CRC.

cancer biology↗

bioRxiv2022

A peptide strategy for inhibiting different protein aggregation pathways in disease

Protein aggregation correlates with many human diseases. Protein aggregates differ in shape, ranging from amorphous aggregates to amyloid fibrils. Possibly for such heterogeneity, strategies to develop effective aggregation inhibitors that reach the clinic failed so far. Here, we present a new strategy by which we developed a family of peptides targeting early aggregation stages for both amorphous and fibrillar aggregates of proteins unrelated in sequence and structure. Thus, they act on dynamic precursors before a mechanistic differentiation takes place. Using a peptide array approach, we first identified peptides inhibiting the predominantly amorphous aggregation of a molten globular, aggregation-prone protein, a thermolabile mutant of the Axin tumor suppressor. A series of optimization steps revealed that the peptides activity did not depend on their sequences but rather on their molecular determinants. The key properties that made a peptide active were a composition of 20-30% flexible, 30-40% aliphatic and 20-30% aromatic residues, a hydrophobicity/hydrophilicity ratio close to 1 and an even distribution of residues of different nature throughout the sequence. Remarkably, the optimized peptides also suppressed fibrillation of Tau, a disordered protein that forms amyloids in Alzheimers disease, and entirely unrelated to Axin. Our compounds thus target early aggregation stages, independent of the aggregation mechanism, inhibiting both amorphous and amyloid aggregation. Such cross-mechanistic, multi-targeting aggregation inhibitors may be attractive lead compounds against multiple protein aggregation diseases.

biochemistry↗