Extreme chromosomal instability in bivalve transmissible cancers

Supervisor: Adrian Baez-Ortega

Most cancers arise from and remain within the bodies of their respective host individuals. Rarely, however, cancers may escape their hosts to become ‘transmissible cancers’ — infectious cell lineages which spread between individuals by direct transfer of cancer cells [1]. As parasitic cancers capable of surviving for millennia, transmissible cancers offer a unique model for exploring how mutation, selection and cellular processes mould and constrain tumour evolution. Marine bivalve molluscs (clams, mussels and cockles) are affected by at least 10 transmissible cancers, known as Bivalve Transmissible Neoplasias (BTNs), which spread via waterborne transfer of living cells. The recurrent emergence of long-lived cancers in these species provides an invaluable resource for comparative studies aiming to probe the mechanisms of tumour evolution. Yet, the processes underpinning genome evolution in BTNs are hardly understood. A recent study investigating the genomes of two BTN lineages in European common cockles [2] uncovered evidence of pervasive chromosomal instability in these cancers, with extraordinary levels of karyotypic plasticity (11–370 chromosomes per cell) even within individual tumours. Chromosomal instability is a phenomenon characterised by aberrant chromosome segregation, which contributes to the evolution of most human cancers and is associated with therapy resistance [3]. While tumours benefit from the disruption of pathways which suppress chromosomal instability, their tolerance of instability is not unlimited. Massive chromosome missegregation is lethal to cancer cells, due to defects induced by imbalanced expression of key mitotic proteins [4]. The ongoing extreme instability of BTN genomes, with levels of chromosome missegregation beyond those observed in human cancers, defies this paradigm, but its underlying mechanisms are unknown. Having evolved under continued instability for hundreds of years, BTN cells likely possess mechanisms for withstanding the toxic effects of this process, offering a natural model to investigate how cancers induce and sustainably manage chromosomal instability.

This research project will leverage large-scale single-cell sequencing data sets and advanced bioinformatic approaches to investigate the following questions:

1. What processes underlie extreme chromosomal instability in BTN cells?

2. What are the evolutionary consequences of chromosomal instability in long-lived cancer lineages? 

Importance of the area of research concerned

Chromosomal instability accelerates tumour evolution and therapy resistance, yet is also deleterious to cancer cells. The lethality of extreme chromosomal instability has prompted its consideration as a potential therapeutic avenue, but direct study of this phenomenon presents challenges. While laboratory models are available, the genetic defects which underlie such models have been found to be extremely rare in human tumours. How chromosomal instability arises in cancers, and why tumours differ in their tolerance of this phenomenon, remains a matter of debate. Given its association with metastasis and therapy failure, understanding the processes responsible for chromosomal instability and tolerance thereof has great oncological relevance. 

Type of work

This project is primarily computational and demands a strong computational and statistical background. The student will leverage large volumes of single-cell DNA sequencing data to study chromosomal instability in BTNs, focusing on two aspects: 1. Processes of chromosomal instability. Using cells obtained from BTN-infected cockles, we will employ shallow single-cell DNA sequencing to derive copy number (CN) profiles for thousands of individual BTN cells. With the aim of investigating the genomic processes driving karyotypic variability in BTN cells, the student will develop and apply computational frameworks to identify CN breakpoints and quantify the stability of such breakpoints both within and across tumours. They will also contrast the patterns of single-cell CN variation in BTN against those observed in human cancers. 2. Consequences of chromosomal instability. Additionally, the student will leverage the single-cell DNA sequencing data to derive empirical background CN distributions, which can be used as statistical nulls to identify genomic segments deviating from expected patterns. Such segments may represent BTN chromosomes possessing efficient segregation mechanisms, or possibly preserved by natural selection because they contain dose-sensitive essential genes. This work will inform on how chromosome biology and selection influence the outcomes of chromosomal instability.

References 

1. Metzger, M. J. & Goff, S. P. A Sixth Modality of Infectious Disease: Contagious Cancer from Devils to Clams and Beyond. PLOS Pathogens 12, e1005904 (2016).

2. Bruzos, A. L. et al. Somatic evolution of marine transmissible leukemias in the common cockle, Cerastoderma edule. Nature Cancer 4, (2023).

3. Lukow, D. A. et al. Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies. Developmental Cell 56, 2427-2439.e4 (2021).

4. Vasudevan, A. et al. Aneuploidy as a promoter and suppressor of malignant growth. Nat Rev Cancer 21, 89–103 (2021).