Measuring chromosomal instability in cancer
Chromosomal instability (CIN) is a key driver of aggressive tumour behaviour. It drives continuous reshuffling of the cancer genome, fuelling intratumour heterogeneity, genome plasticity, and rewiring of immune pathways. CIN has been strongly linked to disease progression, metastasis, and therapeutic resistance across multiple cancer types.
Despite its clinical relevance, CIN is not currently taken into account in routine clinical decision-making, largely because it is difficult to measure accurately.
“When assessing CIN, we currently rely on proxy measures, like genome aberrations, that only provide a static snapshot”, says Dr Beernaert. “CIN is a dynamic process and we need to new methods to disentangle it from its genomic outcomes.”
To address this gap, Dr Beernaert has developed an image-based approach to measure features related to ongoing CIN directly, in clinical-grade tumour samples. Funding from the MSD Pump Priming Scheme will enable him to refine this method by screening new markers and developing deep-learning pipelines to detect CIN-associated features, such as micronuclei.
“By enabling more accurate quantification of ongoing chromosome segregation errors in patient tumours, this project will help establish CIN as a clinically actionable biomarker, while also advancing our mechanistic understanding of how ongoing CIN drives tumour evolution.”
Mapping aggressive tumour niches in gastro-oesophageal cancer
Oesophagogastric adenocarcinomas (OGC) are a group of cancers in which CIN is particularly prevalent and closely associated with poor outcomes.
Research from the Parkes lab and Dr Beernaert's previous work has shown that chromosomally unstable tumours can actively remodel their surrounding environment to support tumour growth. In particular, tumour regions with elevated rates of CIN (CINhigh) show distinct immune microenvironments, with enrichment of suppressive myeloid cells and inflammatory chemokines such as IL-8. However, the precise mechanisms driving these changes remain unclear.
“Oesophagogastric cancer is increasing in incidence in the UK and current treatments are often ineffective. Understanding how CIN drives immune evasion is an important step toward developing novel treatment strategies.”
Importantly, CIN is not evenly distributed throughout tumours, but occurs in distinct tumour islands. This creates regional variation that bulk RNA sequencing approaches fail to capture.
Dr Beernaert has been awarded an Early Career Researcher Development Grant from Guts UK to investigate how CIN shapes the tumour microenvironment within OGC. Building on his image-based CIN detection platform, he will use spatial transcriptomics to map CIN within patient tumour samples and determine the intercellular communication landscape that defines these niches.
“This funding will allow us to build a spatial atlas of chromosomal instability in oesophagogastric cancer. By understanding how unstable tumour islands manipulate their environment, we can begin to design strategies that specifically target these high-risk regions.”
Together, these projects aim to change how we detect and interpret chromosomal instability in cancer. By turning CIN from a marker of poor prognosis into a potential point of intervention, this work could help pave the way for more effective treatments that limit tumour growth and restore immune control.
Dr Beernaert’s work, currently in press at Science Advances, is available as a preprint on bioRxiv: Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS–chemokine–myeloid axis.