Mechanisms and evolutionary significance of hyperploidy variations in a long-lived parasitic cancer

Informations projet

HYPERCAN

N° de convention de subvention: 101116945

DOI

10.3030/101116945

Date de signature de la CE 25 Septembre 2023

Date de début 1 Decembre 2023

Date de fin 30 Novembre 2028

Financé au titre de

• European Research Council (ERC)

Coût total

€ 1 500 000,00

Contribution de l’UE

€ 1 500 000,00

Coordonné par

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Periodic Reporting for period 1 - HYPERCAN (Mechanisms and evolutionary significance of hyperploidy variations in a long-lived parasitic cancer)

Période du rapport: 2023-12-01 au 2026-05-31

Résumé du contexte et des objectifs généraux du projet

Transmissible cancers are fascinating recently discovered biological entities. They have acquired the ability to cross host boundaries and spread between animals, even sometimes interspecifically, by the direct transfer of cancerous cells. In addition, despite asexual reproduction they have been shown to persist for hundreds or thousands of years in host populations. Importantly, in the absence of known sexual-like reproduction mechanism, transmissible cancers must cope with clonal degeneration. One challenging question that arises is to understand the evolutionary processes and molecular mechanisms by which genetic diversity can maintain in such a long-term clonal context. Several transmissible cancer lineages have been described in Bivalvia and they have all in common hyperploidy. Some distinct sub-lineages (with a common founder host) coexist in host populations with specific degrees of hyperploidy (2 to 10 times the host cell DNA content). Hence, the hypothesis that hyperploidization concurs to the persistence and long-term evolution of these transmissible
cancers must be considered. HYPERCAN aims to decipher the evolutionary significance of hyperploidy and of its variation to amplify clonal heterogeneity in mussel transmissible cancers (MtrBTN). We will use a multi-disciplinary approach combining phenotyping and “multi-omics” in order to test evolutionary hypotheses. We will answer 3 main questions: 1. Ploidy and fitness. Does a correlation exist between ploidy degrees and fitness? 2. Evolutionary dynamics. How does evolution proceed in MtrBTN cancers? 3. Hyperploidization mechanisms. How is hyperploidy generated and what is the fate of newly evolved hyperploid lineages? The project will have multiple outputs and applications among which to understand the genetic mechanisms driving the evolution of long-living cancers and to provide useful elements for the assessment of evolutionary and phenotypic effects associated with hyperploidization in cancers.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

To address these questions, we first investigated the distribution, diversity, and biological properties of transmissible cancers affecting mussel populations (Mytilus edulis) along the French coastline. By screening several thousand individuals across multiple sites, we detected infected mussels and estimated a low but consistent prevalence of the disease. Using a combination of complementary diagnostic approaches, we identified two closely related cancer sub-lineages and demonstrated a strong concordance between their cellular and genetic characteristics. These sub-lineages differ notably in their level of DNA content (ploidy), as well as in key cellular features, indicating distinct biological profiles.
By integrating current observations with previously collected samples (since 2017), we reconstructed temporal trends in multiple locations. This revealed a consistent shift over time, with one sub-lineage progressively increasing in frequency while the other declined. This pattern suggests ongoing evolutionary dynamics within natural populations and points to potential differences in fitness between sub-lineages.
To better understand these differences, we performed experimental infections under controlled conditions. These experiments showed that both sub-lineages are capable of being transmitted between individuals, confirming their contagious nature. However, they differ in their biological performance: one sub-lineage consistently exhibits higher transmission success and faster disease progression within the host, supporting the hypothesis that variation in ploidy may be linked to differences in fitness. We also examined the influence of host-related factors and found that they can modulate disease progression, further highlighting the complexity of host–cancer interactions.
In addition, we explored the range of species susceptible to infection. Our results indicate that various Mytilus mussel species and their hybrids can be affected, whereas other marine bivalves tested did not develop the disease. This suggests that, despite its transmissible nature, this cancer remains restricted to a relatively narrow group of closely related hosts.
Finally, the project is generating comprehensive genomic resources to better characterize these transmissible cancers and understand how they evolve over time.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

These first results have been disseminated through participation in the international conference Evolutionary Biology and Ecology of Cancer (Hinxton, UK), as well as invited seminars at the Roslin Institute (University of Edinburgh), the University of St Andrews, and the University of Cambridge.