Title: Molecular coordination between cytoskeletal networks in collective cell migration and its impact on development and disease
Funder: The Academy of Medical Sciences

Abstract: 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.

Lay abstract: Colorectal cancer (CRC) is the second highest cause of cancer death worldwide and is on the increase, especially in developed nations. In the UK, statistics for 2017 show that there were 42,042 new cases and 16,300 deaths. Despite advances, the burden may increase by 30% by 2030. Early detection is key to suppress this trend by increasing the likelihood of successful treatment, with concomitant societal and economic impacts derived from avoiding death or disability from CRC. Alteration of certain genes known as ‘gate-keepers’ promote cancer. One of them known as APC, is altered in more than 85% of CRC cases. In addition, defective APC facilitates other gut diseases (e.g. inflammation, infection). Here I propose various strategies based on the use of models recreating patient responses in the laboratory to study how alteration of APC affects cell movement which in turn is required to maintain normal gut structure. This setup will be used to link specific modes of APC alteration with individual gut diseases. The overall goal of this study is to discover specific biomarkers to permit in the future early detection of the respective gut disorders. Furthermore, a detailed mechanistic understanding of those signatures will advance our ability to develop improved and more personalised therapies.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL