Role of ATRX in colorectal cancer metastasis

Alpha-thalassemia mental retardation x-linked (ATRX) is a chromatin remodelling protein with established roles in regulating chromatin conformation, genomic stability, and homologous repair. ATRX is frequently mutated in many cancer types and in colorectal cancer (CRC) loss of ATRX is associated with the CRIS-B subtype, poor prognosis, and late stage and metastatic disease. There are currently few therapeutic options for patients with metastatic disease and accordingly, very high mortality rates. ATRX loss has been established by the Myant lab as a mediator of plasticity and non-canonical cell states, TGFβ-induced epithelial-to-mesenchymal transition (EMT), and invasion in CRC. These characteristics are thought to promote aggressive and metastatic disease; therefore, the first aim of my project was to determine the effect of ATRX loss on metastasis using mouse models. In addition to this, I wanted to explore the mechanism by which ATRX loss facilitates the observed phenotype, specifically focusing on its role as a chromatin remodelling protein. In this thesis, ATRX loss is demonstrated to drive metastasis in two mouse models and promote a hybrid-EMT phenotype defined by partial loss of epithelial identity, enrichment of a selection of EMT-associated genes (namely TWIST1), and propensity to undergo EMT in response to TGFβ in vitro. I demonstrate that this loss of epithelial gene transcription is driven by loss of chromatin accessibility and transcription factor HNF4α activity at colonic epithelial gene loci. Furthermore, I show that TWIST1 function is required for phenotypic and transcriptional EMT in response to TGFβ. Strikingly, loss of TWIST1 function further enhances metastatic ability of the ATRX knockout model – suggesting that full EMT induction is not required for metastasis. Further characterisation shows that loss of TWIST1 function promotes loss of differentiated cell markers, including a further reduction in epithelial gene expression. I show that this indeterminate cell lineage can be likened to an early embryonic state, which may bestow increased cell plasticity. This requires further investigation but may be supportive of a growing evidence base which underscores the importance of cell plasticity, rather than fixed mesenchymal properties, in fostering metastasis. This project defines ATRX loss as a driver of metastatic disease in CRC and gives insight into the importance of the epigenetic regulation of plasticity and non- canonical cell states in aggressive disease. This contributes to our understanding of the metastatic process and can guide future research identifying novel therapies for metastatic disease.

Grantor dc:publisher

The University of Edinburgh

Year dc:date.issued

2025

Author dc:creator

• Peckett, Nat

Advisors dc:contributor.advisor

• Myant, Kevin
• Steele, Colin

• ATRX
• Metastasis
• Chromatin
• EMT (epithelial-to-mesenchymal transition)
• Plasticity

Language dc:language.iso

en

Identifier URI

http://dx.doi.org/10.7488/era/6288

OAI identifier oai:identifier

oai:era.ed.ac.uk:1842/43755