Authors: Frédéric Thomas, Antoine M. Dujon

Source: BioEssays (Dec 2025)

Abstract

Laplane et al. recently provided a valuable framework for understanding cancer evolution through multilevel selection (MLS), distinguishing between MLS1, where groups differ in persistence based on the traits of their constituent cells but do not reproduce or evolve group-level adaptations, and MLS2, where groups themselves reproduce and possess emergent fitness distinct from that of individual cells. However, as the authors themselves acknowledge, applying MLS2 to metastasis is challenging for several reasons.

We argue that, rather than behaving as isolated evolutionary units, tumor sites function as components of a distributed system. This perspective suggests that metastasis may be better understood through the lens of selection for function, a framework that explains how traits contributing to system-level persistence can be maintained without requiring group-level reproduction.

This approach complements MLS theory and helps account for the resilience of the metastatic system as a whole, namely, the persistence and coordination of multiple tumor sites functioning as a collective rather than as isolated tumors, beyond classical Darwinian models.

It also aligns with the view that metastasis may reflect the reactivation of ancient cellular programs in a novel, nonreproductive context.

Authors: Orsolya Vincze, Piotr Minias, Alexandre Corthay, Fernando Colchero, Jean-François Lemaître, Louise Maille, Tamás Malkócs, Justus Hagemann, Dalia A. Conde, Samuel Pavard, Antoine M. Dujon, Beata Ujvari, Frédéric Thomas, Amy M. Boddy, Carlo C. Maley, Damien Chevallier, Tuul Sepp, Thomas Pradeu & Mathieu Giraudeau

Source: Nature Communications (Nov 2025)

Abstract

Contrary to expectations based on their higher cell numbers, larger and longer-lived species do not face dramatically increased risk of cancer. This strongly suggests that evolution has fashioned natural cancer resistance mechanisms, yet our knowledge remains limited on what these mechanisms might be.

The cancer immunological surveillance hypothesis, proposed by Burnet and Thomas in the 1950s, highlights immunity as a key factor determining species-specific cancer resistance.

Here we address the original, evolutionary interpretation of this hypothesis by investigating the relationship between cancer mortality risk and markers of efficient antigen presentation.

Our results show that the expansion of the MHC class I gene complex, as well as increased selection for diversity at these genes is associated with sharply decreasing cancer mortality risk across mammals.This suggests that the efficient presentation of diverse peptides in somatic cells is important for cancer suppression across mammals, providing pioneering evidence that supports the cancer immunosurveillance hypothesis across species.

Authors: Emily Hann, Debolina Majumdar, Daniel Layton, Mohamed Fareh, David M Cahill, Mark Ziemann, Beata Ujvari, Karel A Schat, Arjun Challagulla

Source: Functional & Integrative Genomics (Nov 2025)

Abstract

The CRISPR-Cas13 system has emerged as a powerful platform for programmable RNA targeting, offering efficient and sequence-specific silencing of coding and non-coding transcripts. The RNA-targeting capabilities of CRISPR-Cas13 have been harnessed to silence transcripts harbouring pathogenic mutations and combat infectious diseases. However, the molecular basis of on-target and collateral activity are not completely understood, limiting the utility of Cas13 systems.

In this study, we delineate the principles for the development of effective crRNAs by targeting DsRed fluorescence reporter and synthetic influenza mRNA in chicken fibroblast DF1 cells. To systematically determine the optimal design for RfxCas13d crRNA, we investigated the minimum length of the crRNA, importance of protospacer flanking sequence, degree of mismatch tolerance, and off target effects.

Our data reveal variable knockdown levels between crRNAs, in which several crRNAs achieved over 95% target knockdown. We show that crRNAs exhibit a high degree of tolerance to single-nucleotide mismatches, regardless of their position in the spacer sequence. However, 4-nt mismatches between the spacer and the target significantly reduces targeting efficacy, whereas eight nucleotide mismatches completely abolish the activity of RfxCas13d. Finally, we compared targeting efficiency and collateral activity of two widely used RfxCas13d and HfCas13d variants.

Our data extend current understanding of Cas13d-mediated RNA targeting and offer a framework for rational crRNA design to enhance effectiveness in diverse applications, including antiviral strategies.

Authors: Frédéric Thomas, Jean-Pascal Capp, Antoine M Dujon, Andriy Marusyk, Klara Asselin, Mario Campone, Pascal Pujol, Catherine Alix-Panabières, Benjamin Roche, Beata Ujvari, Robert Gatenby, Aurora M Nedelcu

Source: Evolution Medicine And Public Health (Aug 2025)

Abstract

Current cancer therapies often fail due to tumor heterogeneity and rapid resistance evolution. A new evolutionary framework, ‘selection for function,’ proposes that tumor progression is driven by group phenotypic composition (GPC) and its interaction with the microenvironment, not by individual cell traits.

This perspective opens new therapeutic avenues: targeting the tumor’s functional networks rather than individual cells. Real-time tracking of GPC changes could inform adaptive treatments, delaying progression and resistance. By integrating evolutionary and ecological principles with conventional therapies, this strategy aims to transform cancer from a fatal to a manageable chronic disease.

Crucially, it does not necessarily require new drugs but offers a way to repurpose existing therapies to impair a tumor’s evolutionary potential. By steering tumor evolution toward less aggressive states, this approach could improve prognosis and long-term patient survival compared to current methods.We argue that leveraging GPC dynamics represents a critical, yet underexplored, opportunity in oncology.

Authors: Justine Boutry, Mathieu Douhard, Klara Asselin, Antoine M. Dujon, Jordan Meliani, Olivier De Backer, Delphine Nicolas, Aaron G. Schultz, Peter A. Biro, Christa Beckmann, Laura Fontenille, Karima Kissa, Beata Ujvari, Frédéric Thomas

Source: Ecology And Evolution (Aug 2025)

Abstract

Offspring sex ratio has been proposed as an indicator of the risk of developing certain cancers in humans, but offspring sex ratio may also be a consequence of the disease.

In this study, we investigate this subject using the zebrafish, Danio rerio, as a model system. First, we explore whether inducing skin cancer at an early stage of the host’s life (embryonic stage) has the potential to influence sex determination and/or sex-specific mortality. Second, we investigate whether the sex ratio in offspring produced by tumor-bearing adult females differs from that of healthy females. Third, we compare the survival (until sexual maturity) of offspring produced by cancerous and non-cancerous females.

We found that skin cancer did not influence sex determination and the sex ratio of the offspring. However, consistent with previous studies on other model systems, the survival of offspring was higher when mothers were cancerous, suggesting that diseased females allocate more resources to current reproductive effort compared to their healthy counterparts.

This study makes a significant contribution to our understanding of the ecological and evolutionary consequences of host-tumor interactions in animals.

Authors: Antoine M. Dujon; Peter A. Biro; Beata Ujvari; Frédéric Thomas

Source: Royal Society Open Science (Jul 2025)

Abstract

The multistage carcinogenesis model predicts that cancer risk should increase with body size and longevity owing to greater cell numbers and divisions, which provide more opportunities for mutations. However, the perceived lack of such associations across species, named ‘Peto’s paradox’, suggests that larger or longer-lived animals may have evolved enhanced cancer suppression mechanisms.

Empirical tests of this paradox have been limited by data availability, but large-scale zoo datasets now enable comparative analyses of cancer prevalence in vertebrates. Currently used statistical methods, however, often fail to adequately account for uncertainty in key model parameters.

In this study, we use Bayesian methods to reanalyse these datasets and explore Peto’s paradox, emphasizing the importance of quantifying uncertainty in comparative oncology. Our results show that body mass is positively associated with malignancy risk in mammals and amphibians, while it is negatively associated with cancer mortality in mammals. Longevity is positively associated with malignancy risk in non-avian sauropsids and amphibians. However, these relationships are accompanied by effect sizes with substantial uncertainty, primarily owing to small sample sizes.

Through simulations, we demonstrate the limitations of current datasets and models. We also discuss the broader implications of Peto’s paradox and suggest recommendations for improving future research on cancer risk across species.

Authors: Audrey Arnal, Erika Burioli, Lisa Jacquin, Sophie Labrut, Stéphane Duchon, Marie Rossignol, Delphine Nicolas, Beata Ujvari, Antoine Dujon, Jordan Meliani, Jérôme Abadie, Frédéric Thomas, Vincent Corbel

Source: Ecotoxicology and Environmental Safety (Aug 2025)

Abstract

Malathion is a widely used pesticide with potentially oncogenic properties and may have deleterious effects on organism health and fitness. Although malathion use is now restricted in the European Union, it remains widely used for public health campaigns in other parts of the world, particularly for mosquito control. Understanding its sublethal and long-term effects is thus essential, both for evaluating its ecotoxicological impacts and for anticipating resistance mechanisms. However, empiric data on its effects in wild organisms – especially in invertebrates – remain limited.

Here, we quantitatively investigated whether larval exposure to environmentally realistic concentrations of malathion could affect mosquito tissue structure and gene expression profiles of adult Aedes aegypti (yellow fever mosquitoes), using both RNA-seq and histological approaches.

Results show no neoplastic or pre-neoplastic lesions in adults exposed to malathion during larval development, contrary to previous studies in other organisms showing carcinogenic effects of malathion. However, our differential gene expression analyses revealed significant changes in genes related to mitochondrial function, energy metabolism, and detoxification pathways, suggesting significant physiological impacts of malathion in adults after early-life pesticide exposure.

Notably, females exhibited stronger transcriptomic responses than males, including the upregulation of genes involved in detoxification (e.g., P450 cytochromes), olfactory perception, and stress response, with potential consequences for resistance mechanisms.

Our findings underscore the ability of mosquitoes to mount transient molecular responses to environmental pollutants, potentially contributing to the long-term selection of metabolic resistance traits – an outcome with important implications for vector control strategies.

Authors: N. Stepanskyy, M. Pascal, K. Asselin, L. Brazier, J. Meliani, S. Tissot, A. M. Nedelcu, J. Tökölyi, B. Ujvari, F. Thomas & A. M. Dujon

Source: Scientific Reports (Feb 2025)

Abstract

Transmissible tumors are increasingly regarded as a new form of parasitic life, but relatively little is known about the ecology and evolution of their interactions with their host. In this work, we provide new insights into transmission dynamics of vertically transmitted tumors in the freshwater cnidarian Hydra oligactis.

First, we found tumoral hydra to be infectious at any age, regardless of whether they were in their asymptomatic or symptomatic phases, with the bacteriome composition remaining constant during both phases. Interestingly, tumor transmission increased with the number of tentacles, particularly for hydras with supernumerary tentacles.

Additionally, tumors developed earlier in the offspring from parents with more advanced tumors. Furthermore, despite being direct descendants of tumoral polyps, some hydras never developed tumoral phenotype. The latter exhibited a distinct bacteriome composition, reduced lifespan and a lower tentacle number increase over time. Interestingly, the tumor phenotype expression in these hydras appears to be able to skip generations, as transmission occurred at any age from parents to offspring.

We discuss these results in the context of current knowledge on the evolutionary ecology of host-transmissible tumor interactions as well as parasite-host interactions and suggest avenues for further research.

Authors: Gregory P Brown, Thomas Madsen & Richard Shine

Source: Oecologia (Mar 2025)

Abstract

Males and females within a population may differ in dietary composition either as a non-adaptive consequence of sexual dimorphism, or because specific food types enhance fitness more in one sex than the other. To test between those two explanations, we can ask whether the consumption of a food type (a) is constrained by sexually dimorphic traits such as body size, or (b) differentially benefits the sex that consumes that food more frequently.

A 23-year field study of Slatey-Grey Snakes (Stegonotus australis) in tropical Australia provided data on 663 meals, of which 130 were reptile eggs (primarily from Keelback Snakes (Tropidonophis mairii)).

Over the same range of snake SVLs, eggs were consumed more often by female than by male Slatey-Grey Snakes (25.8 versus 15.2% of records), but consumption of reptile eggs was independent of snake body size. Female Slatey-Grey Snakes were not more common or more active than males during Keelback nesting periods, but they were more likely to be captured in the vicinity of Keelback oviposition sites than were males. In years with higher availability of Keelback eggs, female Slatey-Grey Snakes had higher clutch sizes and clutch masses (plausibly reflecting the nutritional benefits of eating reptile eggs to provision reptile eggs).

In combination, our results suggest an adaptive basis to the sex-based divergence in dietary composition in Slatey-Grey Snakes.

Authors: Justine Boutry, Océane Rieu, Lena Guimard, Jordan Meliani, Aurora M Nedelcu, Sophie Tissot, Nikita Stepanskyy, Beata Ujvari, Rodrigo Hamede, Antoine M Dujon, Jácint Tökölyi & Frédéric Thomas

Source: eLife (Mar 2025)

Abstract

While host phenotypic manipulation by parasites is a widespread phenomenon, whether tumors – which can be likened to parasite entities, can also manipulate their hosts is not known. Theory predicts that this should nevertheless be the case, especially when tumors (neoplasms) are transmissible.

We explored this hypothesis in a cnidarian Hydra model system, in which spontaneous tumors can occur in the lab, and lineages in which such neoplastic cells are vertically transmitted (through host budding) have been maintained for over 15 years. Remarkably, the hydras with long-term transmissible tumors show an unexpected increase in the number of their tentacles, allowing for the possibility that these neoplastic cells can manipulate the host.

By experimentally transplanting healthy as well as neoplastic tissues derived from both recent and long-term transmissible tumors, we found that only the long-term transmissible tumors were able to trigger the growth of additional tentacles. Also, supernumerary tentacles, by permitting higher foraging efficiency for the host, were associated with an increased budding rate, thereby favoring the vertical transmission of tumors.

To our knowledge, this is the first evidence that, like true parasites, transmissible tumors can evolve strategies to manipulate the phenotype of their host.