Persistent pathological structures, such as tumors, fibrotic nodules, granulomas, microbial biofilms, or protein aggregates, are traditionally viewed as age-related conditions that emerge after reproduction, when natural selection is less effective at eliminating traits expressed late in life. However, some pathologies with robust and organized architectures can arise surprisingly early, challenging this classical perspective. We recently proposed that intra-organismal selection for function, a selective process operating within organisms and acting on non-reproducing entities by favoring structural configurations that enhance stability, robustness, and novelty generation, may play a role in aging. Here, we suggest that this same process can also operate well before the so-called selection shadow (i.e., life stages where natural selection is too weak to purge deleterious mutations). We identify three non-mutually exclusive mechanisms that may promote this early-life action: (i) initial local adaptive benefits, such as improved tissue repair or containment of infection; (ii) limited or context-specific fitness costs, allowing structurally stable but abnormal configurations to persist undetected; and (iii) rapid environmental changes that reshape tissue-level selective landscapes, driven by pollutants, endocrine disruptors, or novel diets. Recognizing early-onset organized pathologies as by-products of eco-evolutionary tissue dynamics, rather than as mere developmental errors, reframes their biological significance and opens new therapeutic avenues. Instead of targeting cells exclusively, future strategies could focus on disrupting the functional architecture of pathological tissues and structures, offering novel means to prevent or control early-life diseases shaped by internal selection forces.

Environmental changes can disrupt long-standing host-symbiont associations and influence tumor dynamics; however, how these two aspects interact remains poorly understood, particularly when previously co-evolved symbionts are reintroduced into tumor-prone hosts. We experimentally reintroduced a native commensal ciliate symbiont (Kerona pediculus) into two long-term cultured symbiont-free lines of the freshwater cnidarian, Hydra oligactis, differing in tumor affliction: one harbors a transmissible tumor, and one has historically low spontaneous tumor incidence. Unexpectedly, spontaneous tumors emerged at high frequency in the latter, independently of ciliate acquisition, fundamentally reshaping the experimental framework and enabling comparisons of how symbiont reintroduction affects hosts with either transmissible or de novo tumors. While ciliate infection did not alter tumor incidence, it slightly accelerated tumor onset, increased the likelihood of supernumerary tentacle formation, and reduced asexual reproduction (particularly at high symbiont densities) across tumor contexts. Spontaneous tumors appeared later than transmissible tumors, were less often associated with supernumerary tentacles, and induced an earlier reproductive burst. Our findings show that symbiont reintroduction and tumor context shape tumor dynamics and life-history traits in tumor-bearing hosts, emphasizing the potential role of symbiotic history and tumor evolutionary context when assessing the outcomes of such pressures in vulnerable host populations.

Pathological processes are often conceptualized as localized phenomena anchored in a primary tumor, a focal lesion, or a single organ. However, growing evidence indicates that many diseases persist and progress as complex distributed systems, maintained by interactions among multiple sites. Building on the emerging framework of selection for function, which can be applied to understand the evolutionary persistence of both replicating and non-replicating entities, we propose that metastases, amyloidoses, fibroses, autoimmune syndromes, granulomatous diseases, and multifocal reproductive disorders can all be understood as complex evolving pathological systems within individuals. In these contexts, local units such as metastatic nodules, amyloid plaques, or fibrotic foci act as semi-autonomous entities, yet achieve collective persistence through systemic flows, feedback loops, and network-level interactions, where local structuration gives rise to systemic effects. At certain points, lesions that produce mediators can trigger systemic alterations that, in turn, favor the emergence and persistence of additional lesions. This creates a vicious cycle in which local and systemic dynamics reinforce one another, helping these specific pathological networks to overcome host defense mechanisms and persist (i.e., be 'selected' via differential persistence). This perspective unifies seemingly disparate conditions under the principle of system persistence, reframing pathology as an emergent organizational property of a pathological system rather than as isolated local breakdowns of organismal components. It also carries important implications for evolutionary medicine, suggesting a taxonomy of diseases that distinguishes localized from distributed functional pathologies. Clinically, it underscores the need to go beyond focal interventions, advocating instead for therapies that disrupt pathological connectivity, destabilize network coherence, and monitor systemic biomarkers of disease persistence. Recognizing the role of selection for function in the emergence and persistence of complex pathological systems opens new avenues for both theoretical integration and therapeutic innovation in evolutionary medicine.

Many cancer therapies achieve durable control without complete tumor eradication, suggesting that disrupting tumor organization may be more critical than killing cells. We propose that effective treatments converge by destabilizing the tumor's Group Phenotypic Composition (GPC), the functional and spatial organization of interacting cell populations. When this organization collapses, tumors lose coherence. This perspective provides a unifying framework for designing therapies targeting tumor-level dynamics rather than cell number alone.

Devil Facial Tumour Diseases (DFTD), threatening Tasmanian devils, consist of two distinct transmissible cancers, DFT1 and DFT2, with differing origins and geographic spread. We investigated the metabolic differences between DFT1 and DFT2, examining cell viability, metabolic outputs, and bulk gene expression. Using both DFT1 and DFT2 cell lines and biopsies, we found that glycolysis, oxidative phosphorylation, glutamate metabolism, and fatty acid synthesis are all essential for the survival of both tumour types. However, DFT2 exhibited higher rates of glycolysis and lactate generation compared to DFT1. This coincided with elevated ATP production, cholesterol biosynthesis, and ROS generation, as well as an increased reliance on fatty acid metabolism. Furthermore, DFT2 is less metabolically adaptable than DFT1, being unable to switch to oxidative phosphorylation as DFT1 can when required. These metabolic changes in DFT2, in conjunction with its higher growth rate, suggest a more aggressive cancer phenotype than DFT1. Our findings highlight distinct metabolic adaptations in DFT2 that may contribute to its competitive advantage.

Reproduction is a key life-history trait but often comes at the expense of somatic maintenance, including ageing and susceptibility to disease. While reproduction-immunity trade-offs have been experimentally demonstrated in the context of infectious diseases, whether reproduction similarly undermines susceptibility to tumours has remained unclear. Using the freshwater cnidarian Hydra oligactis, in which tumours arise spontaneously and reproductive effort can be experimentally modulated through food availability, we tested the possibility of a trade-off between reproduction and tumour dynamics. Higher reproductive effort increased the likelihood of tumour development, reduced the probability of remission and increased the likelihood of progression to advanced stages. Resource availability modulated the strength of the trade-off in terms of tumour risk and remission, whereas tumour severity was determined solely by reproductive effort. Together, these findings provide rare empirical support for a trade-off between reproduction and tumour dynamics, demonstrating that reproductive investment compromises both tumour prevention and control and that its expression can be shaped by environmental conditions. More broadly, they suggest that cancer susceptibility in more complex lineages may instead reflect evolutionary trade-offs that prioritize reproduction over somatic maintenance, helping illustrate one mechanism by which evolutionary trade-offs contribute to the persistence of cancer and to variation in susceptibility across taxa.

Pharmaceuticals are pollutants that affect ecosystems and organism health, yet research on their trophic transfer remains limited, and often restricted to a few drug classes. Endorheic lakes, with minimal water outflow, provide an ideal but understudied setting for such investigations. We investigated eight pharmaceuticals in an effluent-influenced endorheic lake system in southeast Australia. Across four seasonal sampling events, we collected surface water samples, flora samples from five species (including Phragmites australis and Alisma lancelolatum), samples from fauna, including glass shrimp, Paratya australiensis, three fish species (Cyprinus carpio, Gambusia affinis, Galaxias spp.), and invertebrates including spiders (Tetragnathidae). We found that seven of the eight pharmaceuticals analysed were detected in the surface water, flora and fauna. Concentrations ranged from at the limit of quantification (0.3-5 ng/L, all pharmaceuticals) to 159 ng/L (for tramadol). Concentrations decreased with distance from the outfall, posing a low risk for the environment. We detected pharmaceuticals in all biota except glass shrimp, with concentrations up to 1.5 ng/g (Carbamazepine in Phragmites australis). Pharmaceutical concentrations in Phragmites australis showed a unimodal relationship with leaf age. Food web analysis identified significant dilution of tramadol in the food web (trophic magnification factor = 0.72, p = 0.046), while no significant trophic movement was seen for carbamazepine (1.0). This is the first study to quantify and validate trophic magnification factors for a selection of pharmaceuticals in an Australian aquatic ecosystem. The results underscore a critical need to broaden investigation of pharmaceutical trophic magnification across inland lakes.

Despite decades of cancer research, the stage of life at which cancerous processes lead to tumor formation in various organs remains poorly understood. This uncertainty largely stems from the lack of systematic monitoring of organs across different life stages, resulting in tumors often being detected at various stages of development and making it difficult to determine when they initially emerged and began to grow. Moreover, individuals in real-world settings are exposed to diverse environmental factors that generate substantial inter-individual variability, as lifestyle undeniably contributes to tumorigenesis. To address this gap, we performed regular histological monitoring of tumoral processes in wild-derived laboratory strain mice maintained under standardized laboratory conditions. We specifically compared three small endocrine organs (ovary, thyroid, and adrenal glands) with four larger organs (lung, liver, mammary gland, and kidney) at different time points across the animals' lifespan. To introduce realistic genetic variability, we initially crossed wild-derived inbred laboratory strains. Our findings reveal that the earliest signs of tumor development do not appear before 18 months of age, which is relatively late in the lifespan of these outbred individuals. These results support the view that cancerous processes predominantly emerge in late life and suggest that heterozygosity provides a protective effect, while emphasizing that tumor development remains shaped by interactions with the tissue microenvironment even under controlled conditions.

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.

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.

Aging, and by extension age-related diseases, has traditionally been understood through classical evolutionary genetic models, such as the mutation accumulation and antagonistic pleiotropy theories. However, these frameworks primarily focus on the declining efficacy of organismal-level selection against mutations with deleterious effects in late life. Here, we propose a novel hypothesis: many chronic diseases associated with aging may emerge, at least in part, as a result of selection acting at lower organizational levels, including non-replicative biological entities, enabled by the relaxation of selective pressures that constrained within-organism evolutionary processes in early life. This hypothesis is built on the recently proposed concept of selection for function that extends the evolutionary process to non-replicative entities. While Darwinian selection acting at the organismal level strongly constrains within-organism evolution during an organism's reproductive lifespan, these constraints weaken with age. As a consequence, lower-level non-replicative entities, such as benign and malignant tumors, atherosclerotic plaques, and neurodegenerative aggregates, may experience a form of selection that favors those with increased stability, organization, and long-term persistence, sometimes at the cost to host fitness. These entities do not evolve via long-term differential reproduction, but rather certain configurations of their structure persist preferentially over others due to environmental constraints, microenvironmental selection, and internal stabilization mechanisms. Understanding aging through the lens of selection for function at the level of internal non-replicative entities provides new insights into the evolution of chronic diseases and opens novel therapeutic avenues aimed at disrupting internal functional organization, rather than merely targeting cellular proliferation/abnormalities or disease symptoms.

Oncogenic pressures, factors that increase tumor risk, are intensifying with human-driven environmental change, yet their ecological effects remain mainly unquantified. We examined how UVB-induced oncogenic stress affects interactions between two Australian freshwater planaria: the globally invasive predator Girardia tigrina and the native prey Cura pinguis. We hypothesized that DNA damage could either heighten prey vulnerability or impair predator performance. Native planaria showed less UVB-induced DNA damage, likely due to darker pigmentation, while damage in G. tigrina reduced predation rates, suggesting energetic costs of DNA repair. UVB also reduced movement in both species, with partial recovery in the invasive species but prolonged immobility in the native. Additionally, UVB strongly suppressed asexual reproduction in G. tigrina, indicating trade-offs between DNA repair and proliferation. These results reveal that oncogenic stress can reshape species interactions and invasion dynamics, underscoring the need to integrate cancer ecology into conservation and invasion biology.

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.

The recurrence of clinically advanced cancers is an evolutionary consequence of standard-of-care chemotherapies generally administered at maximum tolerated doses to kill as many cancer cells as possible. The inevitable appearance of resistance raises the possibility of shifting treatment goals from complete tumor eradication to long-term disease control. The latter approach is employed by adaptive therapy, which aims to inhibit the evolutionary dynamics governing the spread of resistant tumor phenotypes. Adaptive therapy changes focus from the cancer cells that are responsive to therapy to those that are resistant and ultimately govern outcome. This therapeutic approach retains a pool of sensitive cancer cells to compete with the therapy-resistant ones through dynamic dose modulation and/or timing. Thus, fluctuations of treatment-sensitive cells are used to control the resistant population and prolong tumor control with existing therapy agents. Here, we explore non-genetic mechanisms of resistance, including the protective role of the tumor stroma, the epithelial-to-mesenchymal transition, the overexpression of drug efflux pumps, and the extracellular vesicle-mediated transfer of them. These mechanisms can increase the size of the resistant population at the expense of the sensitive one, reducing the ability of adaptive therapy to force tumor evolution into controllable cycles.

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.

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.

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.

AbstractWhile most cancers are not transmissible, there are rare cases where cancer cells have acquired the ability to spread vertically or horizontally to other individuals, and sometimes species, causing epidemics in their hosts. However, as these transmissible cancers are usually detected once they are relatively well disseminated in host populations, the conditions associated with their origin remain poorly understood. Using the freshwater cnidarianHydra oligactis, which exhibits spontaneous tumor development that in some strains became vertically transmitted, this study presents the first experimental observation of the evolution of a transmissible tumor. Specifically, we assessed the initial vertical transmission rate of spontaneous tumors and explored the potential for optimizing this rate through artificial selection. One of the hydra strains, which evolved transmissible tumors over five generations, was characterized by analysis of cell type and microbiome, as well as assessment of life-history traits. Our findings indicate that tumor transmission can be immediate for some strains and can be enhanced by selection. The resulting tumors are characterized by overproliferation of large interstitial stem cells and, in contrast with other transmissible tumors on Hydra, are not associated with a specific microbiome. Furthermore, although tumor transmission has only been established over 5 generations, it was sufficient to alter life-history traits in the host, suggesting a compensatory response. This work, therefore, makes the first contribution to understanding the conditions of transmissible cancer emergence and their short-term consequences for the host.

A quarter of marine mammals are at risk of extinction, with disease and poor habitat quality contributing to population decline. Investigation of the Major Histocompatibility Complex (MHC) provides insight into species’ capacity to respond to immune and environmental challenges. The eighteen available cetacean chromosome level genomes were used to annotate MHC Class I loci, and to reconstruct the phylogenetic relationship of the described loci. The highest number of loci was observed in the striped dolphin (Stenella coeruleoalba), while the least was observed in the pygmy sperm whale (Kogia breviceps) and rough toothed dolphin (Steno bredanensis). Of the species studied, Mysticetes had the most pseudogenes. Evolutionarily, MHC Class I diverged before the speciation of cetaceans. Yet, locus one was genomically and phylogenetically similar in many species, persisting over evolutionary time. This characterisation of MHC Class I in cetaceans lays the groundwork for future population genetics and MHC expression studies.