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Tissue adaptations to colitis influence neoplastic risk through clonal interaction



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Moutin, Elisa 


Despite a significant fraction of worldwide cancer cases being linked to chronic inflammation, full understanding of the neoplastic process in this context is lacking. The profound tissue remodelling described in chronic inflammatory diseases suggests that alteration of reciprocal signalling between the epithelium, stroma and extracellular matrix participates in the pathogenesis of such illnesses. With the work presented in this thesis, I aimed to determine the impact of tissue alterations on neoplasia in the context of Inflammatory Bowel Disease.

Tissue adaptations were described in the Muc2KO model of colitis, including profound remodelling of the extracellular matrix compartment pre-pathology and during active disease. Upregulation of small-leucine-rich proteoglycans was found to be an early adaptation to colitis, whilst this class of proteins was seen downregulated in advanced disease. At this later stage, modulated interactions were identified between matrisomal ligands and receptors mapping to recruited cell populations, revealing the extent of matrisomal orchestration of tissue remodelling and highlighting their potential as treatment targets in the context of Inflammatory Bowel Disease.

Colitis in the Muc2KO model triggered epithelial adaptation in the form of neutral clonal expansion necessary for tissue regeneration. Introduction of cancer-driver mutations in Trp53 and Kras in a Muc2KO background had limited impact on survival and pathology, which drew interesting parallels between tissue regenerative processes and cancer initiation. Such processes were explored in depth after chemical mutagenesis in the Muc2KO model, where both anti-inflammatory and cancer-driver mutations were shown to benefit from the permissive chronically inflamed environment for expansion. Regenerative expansions did not seem to compete with cancer-drivers for space, and evidence was presented for potential synergy between the two types of expansions.

Therefore, early intervention in IBD is key to prevent tissue adaptations that will lead to colitis-associated-cancer. In this context, remodelling of the extracellular matrix such as upregulation of small-leucine-rich proteoglycans could be an indicator to start treatment immune modulating treatment, whilst the switch to their downregulation could indicate the need for more aggressive intervention, such as surgery.





Winton, Douglas


Cancer, Extracellular matrix, Inflammatory Bowel Disease, Stem cell


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Cancer Research UK (S_4120)