Defining the origins and vulnerabilities of cancer chromosomal instability

Background Cancer genomes exhibit extensive chromosomal alterations caused by ongoing Chromosomal Instability (CIN) including DNA copy number alterations and structural variation.

The ensuing cell-cell heterogeneity facilitates evolution and cancer cell plasticity that can drive therapy resistance but the origins of CIN, and how this tumour-specific vulnerability could be targeted, remain unknown.

Crucially, the field lacks both: (i) a ground truth with which to decode ongoing CIN mechanisms from tumours exhibiting myriad genomic alterations, and (ii) a knowledge of therapeutic vulnerabilities associated with specific CIN mechanisms.

Aims We will systematically determine how specific chromosomal instability mechanisms disrupt the human genome, characterise the ongoing genomic alterations in cancer, and search for new synergies between specific CIN mechanisms and therapies as essential steps towards exploiting chromosomal instability to treat cancer.

Methods We will use controlled experimental induction of a wide range of individual and specific CIN processes that are putative drivers of cancer CIN.

We will use single cell and long-read sequencing and optical genome mapping to determine the copy-structural genomic alteration impact on the genome of each CIN driver.

We will implement a novel single cell genome readout CRISPR screen, complemented by individual gene knockouts and overexpression systems to analyse a wide range of CIN drivers efficiently.

In parallel, we will characterise the genomic alterations caused by ongoing CIN in physiologically relevant cancer models (primary cell lines, organoids and syngeneic murine models) spanning multiple cancer types. We will identify and validate new CIN driver:synergies using syngeneic immuno-competent mouse models.

How the results of this research will be used Our research program will systematically uncover the mechanistic origins of copy-structural variations arising from diverse chromosomal instability (CIN) processes.

We will also identify novel therapeutic synergies with specific CIN mechanisms, filling critical gaps in the field of personalised cancer therapy guided by CIN signatures.

Importantly, companies like Tailor Bio and Volastra are poised to translate our discoveries into tangible benefits for cancer patients.

Our ultimate aim is to significantly enhance our ability to identify CIN mechanisms from single cell or bulk sequencing, revolutionising our capacity to infer CIN drivers from various tumour samples, including cancer or pre-cancer biopsies and thousands of sequenced tumour genomes.

This research is vital to Cancer Research UK because identifying additional CIN drivers holds promise for developing innovative combination therapies with matching genomic biomarkers, similarly to the success of targeted agents exploiting vulnerabilities in homologous recombination repair and replication stress.