Abstract
Colorectal cancer (CRC) is the 3rd most common cancer worldwide, and the 2nd most common cause of cancer death. Despite new advances in treatments andtechnologies, the burden may increase significantly in the next 20 years. CRC is a
malignant gastrointestinal disease caused by genetic changes in the colonic
epithelium. Therefore, it is vitally important to know the molecular mechanisms that regulate epithelial polarity, controlling the phenotype, motility, and aggressiveness of tumour cells. Gut epithelium maintenance depends on a combination of factors, including cell proliferation and apoptosis, differentiation and active cell migration, adhesion to neighbour cells, and the basal membrane. All these processes rely on the fine-tuning function of the actin cytoskeleton.
Actin cytoskeleton dynamics is governed by a network of proteins. One of those
proteins is the tumour suppressor Adenomatous Polyposis Coli (APC), well-known as the gatekeeper in colorectal cancer. APC, through its C-terminal basic region, interacts with cytoskeletal networks. Recent findings have linked APC’s cytoskeletal interactions in cell adhesion and migration. Despite the importance of APC in human health, whether APC-driven actin activity contributes to any collective cell migration event in gut homeostasis and/or impacts on health is unknown. In this thesis, I start to decipher whether APC-driven actin nucleation has a role in cell remodelling and, consequently, collective migration of colorectal cancer cells.
To do that, I used a separation-of-function mutant of APC incapable of nucleating actin and that only changes two residues of the entire protein (APC-m4) coupled with molecular and cellular biology assays and several bioimaging techniques, both in 2D monolayers and 3D spheroids as model systems.
I found that APC-driven actin nucleation activity at cell junctions contributes to the integrity of the cell-cell junctions and collective cell migration on monolayers. These findings translated to the gut suggest that this APC activity may help to support the integrity of the epithelial barrier and the collective active migration of cells along the gut. Moreover, I also found that this pool of actin not only has a crucial role in the biogenesis of invasive protrusions that break the extracellular matrix, allowing cells to detach from the main tumour and invade other tissues, but also contributes to the generation of the traction forces that promote the formation of those protrusions.
Together, these insights underscore the importance of further studying APC’s
cytoskeletal functions and their potential as therapeutic target for interventions aimed at preventing colorectal cancer progression.
| Date of Award | 2 Apr 2025 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Maria Angeles Juanes Ortiz (Supervisor) & Claudio Angione (Supervisor) |