FlexCAT Training program to engage flexible and disordered protein targets for therapeutic development: The oncogene β-catenin as showcase
MARIE SKŁODOWSKA-CURIE ACTIONS Project 101311592 Dr. Nicolas Leveille University Medical Center Amsterdam
Project Title: Phenotypic and molecular changes driven by β-catenin inhibitors in colorectal cancer (CRC)
Objectives: 1. Evaluate the influence of β-catenin inhibitors on the Wnt pathway. 2. Assess phenotypic and transcriptional changes of β-catenin inhibitors in a panel of CRC cell lines. 3. Uncover β catenin/RNA interactome changes mediated by β-catenin inhibitors.
Project Overview: Activation of β-catenin transcriptional program occurs in approximately 80% of CRC patients, which highlights the central role of Wnt signaling in CRC. Importantly, β-catenin orchestrates specific transcriptional changes through the formation of nuclear condensates, which in turn are organized by the intermolecular interactions mediated by β-catenin’s IDRs. While inhibition of β catenin remains elusive, novel therapeutic approaches to interfere with its function are of great importance in the context of CRC.
We aim to evaluate the potential influence of novel β-catenin inhibitors on the activation of Wnt signaling. Initial efforts will validate the function of these inhibitors by monitoring Wnt signaling changes through various reporter systems (e.g., TOP-Flash and TOP-GFP) and transcriptional impact on Wnt target genes. Strong inhibitors will then be studied for their phenotypic impacts (e.g., clonogenicity and proliferation) and global influence on transcription (GRO seq) in CRC cell lines.
We also aim to explore how these inhibitors impact β-catenin/RNA interactions and how this might tie to the formation of condensates. Functional assessment of β-catenin inhibitors will include β-catenin binders developed in WP2 and WP5. Molecules with strong inhibitory functions can be used to identify key features and improve the design of new β-catenin binders. This project has potential to discover novel β-catenin inhibitors with translational potential in CRC, as well as in other cancer types.
Contribution to the overall research program: Functional readout of the effect of designed β-catenin inhibitors on Wnt-signalling.
Salary: The position is funded by the Horizon Europe MSCA-DN project FlexCAT (Grant Agreement No. 101311592) for three years. The selected candidate will be offered a competitive salary comprising a Living Allowance (adjusted by the country correction coefficient), a Mobility Allowance, and, if applicable, a Family Allowance. All allowances are subject to applicable social security contributions and taxation.
Planned secondment: 1. Host: UMI; Supervisor: Prof. Tiziana Bonaldi; Length: 2 months.
Purpose: MS analysis of response to β-catenin interactome modulation.
Enrolment in Doctoral degree(s): UVA (Leveille)
