Molecular coordination between cytoskeletal networks in collective cell migration and its impact on development and disease

The overall goal of this research is to gain in-depth understanding of the molecular mechanisms underpinning gut disorders to ultimately discover new biomarkers for early detection and develop targets for personalised therapies.

This research uses the tumour suppressor Adenomatous Polyposis Coli (APC) as a pivotal prototype to elucidate how cytoskeletal integration supports collective cell movement and how its derangement leads to devastating human diseases.

In contrast to other investigations, this research will generate novel separation-of-function APC mutants and will exploit them in a multi-pronged approach across scales – from single molecule to human intestinal organoids - using cutting-edge microscopy techniques, including multi-color single molecule TIRF microscopy, FRAP, FLIM-FRET, STED and confocal time-lapse microscopy.

The specific aims are: (1) Elucidate the critical residue(s) on APC that directly bind microtubules, and investigate mechanisms underlying this interaction in vitro. (2) Investigate the importance of APC in coordinating cytoskeletal activities (actin and microtubules) in tissue remodelling and collective migration in 2D and 3D biological environments.

Findings in 2D migration using cell lines will be validated and further investigated in 3D-migration using spheroids, as well as in human intestinal organoids which recapitulate patient responses and can be also used for drug screening.

My strategy will link specific mutations and their preclinical consequences with APC molecular understanding, with the goal of discovering genetic signatures for new biomarkers in gut disorders.

Further, these studies will serve as paradigm to address cytoskeletal regulation mediated by multifunctional proteins, beyond APC, also critical for a host of fundamental processes.