Advancing cancer research via comparative oncology

Abstract

In the ongoing battle against cancer, the natural world provides promising inspiration for designing novel therapeutic strategies. The field of comparative oncology offers a valuable source of such inspiration. By combining evolutionary biology, ecology, veterinary medicine, and clinical oncology, comparative oncology aims to better understand cancer, especially by highlighting taxa that are strongly resistant or susceptible to cancer and to identify the molecular and cellular mechanisms underlying the remarkable cancer resistance of some taxa. Such studies hold profound implications for human cancer research and treatment and increase the probability of detecting therapeutic avenues that are non-toxic to healthy cells and tissues. This Perspective underscores the importance of comparative oncology, emphasizes its relevance, and showcases recent breakthroughs in identifying natural cancer resistance mechanisms and opportunities for clinical translation. We advocate for a better integration of cancer research on non-conventional model species into oncology and we urge enhanced cooperation between clinicians and comparative oncologists to advance cancer prevention or treatment strategies.

Table of Contents summary

Comparative oncology combines evolutionary biology, ecology, veterinary medicine, and clinical oncology to better understand cancer, for example, by identifying the molecular and cellular mechanisms underlying the remarkable cancer resistance of some taxa. Therefore, this Perspective by Vincze et al. calls for the increased use of non-conventional model organisms in cancer research to advance cancer prevention and treatment strategies.

Introduction

The landscape of cancer research is evolving rapidly, driven by the mounting prevalence of the disease and by new hopes of finding effective treatments for patients. The field of comparative oncology broadens the conventional view of cancer by shedding light on manifestations of this disease across the tree of life, including mechanisms of its initiation and progression and different resistance mechanisms on a broad scale. Comparative oncology has two main driving goals. The first is to offer a deeper and more integrative understanding of what cancer is. The second is to find novel treatments for patients, by drawing inspiration from natural cancer resistance mechanisms that have evolved in diverse species. Comparative oncology has deep historical roots. Comparisons of tumorigenic processes and discussions over possible common etiologies in humans, animals, and even plants have been taking place since the late 19th and early 20th centuries (e.g., ^1,2). Nonetheless, this approach has been largely overlooked, hindering the possibility of drawing fruitful lessons for the clinic. Thus, it is now critical to showcase the value of comparative oncology in order to promote crosstalk between cancer researchers and oncologists.

In this Perspective, we reflect on thirty years of modern comparative oncology and highlight five key insights that can be gleaned from studying cancer across a variety of species. We underscore the invaluable contribution of both truly comparative studies (i.e., offering comparisons over a wide range of taxa) and species-specific investigations (i.e., focusing on individual non-standard model organisms with unique cancer risk or resistance mechanisms). These approaches not only advance our understanding of cancer from molecular, physiological, and evolutionary perspectives, but may also serve as a source of inspiration for innovative cancer therapies in both human and veterinary oncology.

Cancer is an ancient disease

Cancer represents the second leading cause of mortality in humans, with incidences projected to increase in the coming decades³. However, contrary to common perception, cancer is not a modern disease. The ancient history of cancer is emphasized by fossilized and mummified records of neoplasia. Evidence of tumors has been found in extinct species such as dinosaurs^4,5, giant sloths⁶ and ancestral turtles⁷, where bones dating from 150–240 million years ago are suspected to have been affected by cancer, sometimes with morphology characteristic of human metastatic tumors⁵. In a study comprising around 10,000 bone specimens, it was shown that cancer affected dinosaurs from the hadrosauridae family, with evidence of metastases in the Edmontosaurus genus⁴.

More closely related to modern humans, evidence of cancer has been repeatedly found in extinct species of homini living 1.8–1.6 million years ago⁸. The oldest written mention of cancer in our own species lies in the Edwin Smith Papyrus, a medical text from ancient Egypt likely written in 3000 Before Common Era (BCE)⁹. It describes eight cases of breast tumors that were removed by cauterization. More recently, a rectal cancer has been diagnosed in an Egyptian mummy of the Ptolemaic period (200 Common Era (CE) to 400 CE)^10,11.

The scarcity of examples of cancer in ancient times should be understood in context. Most tumors do not affect the bones (which is the only tissue that is generally well preserved during fossilization) or affect the bone interiors, making it more difficult to detect them in ancient specimens. Challenges lie in distinguishing actual bone tumors from other bone-related diseases or injuries in fossils, with soft tissue malignancies being even more difficult to determine based on ancient skeletal remains¹². Furthermore, bone tumors increase the fragility of skeletal elements, leading to a decreased probability of preservation⁶. Despite these challenges, the available data strongly indicate that cancer has existed for millions of years in a wide range of taxa.

Cancer is widespread across animals

While clinical oncology logically focuses on humans and their close mammalian relatives, the premise of comparative oncology is that much may be learned by extending the scope of cancer research across a broader phylogenetic spectrum. Cancer is known to occur in a very wide range of non-human animals. In non-mammalian vertebrates, unambiguous cancers are found in birds, amphibians, reptiles, and fish¹³. Cancer-like phenomena are also seen in invertebrates, as described below^1,14.

Cancers in nondomestic animals are increasingly documented through surveys based on data from zoos¹⁵ and recently from wild populations¹⁶. Crucially, zoo-based studies have shown significant variance in cancer risk in different species^15,17. For instance, certain carnivorous marsupials have an exceptionally high risk of cancer-associated mortality (as much as 57% in the Kowari), while even-toed ungulates (such as deer or giraffes) generally have very low risks¹⁵. Carnivores overall are more prone to cancer-associated mortality than animals with other lifestyles, which raises interesting perspectives on the impact of diet on cancer. Amongst many other insights, these surveys highlight animals that show unusually high or low cancer rates and can prompt targeted studies to uncover the underlying mechanisms of cancer susceptibility or resistance (see related discussion below). Moreover, comparative studies underscore how animals across the phylogenetic tree exhibit very different patterns of neoplasia (Box 1), not just in cancer risk, but also the proportion of benign and malignant tumors¹⁸, as well as the risk of mortality associated with these¹⁵. For instance, birds, reptiles and amphibians appear better protected against all tumor types, including malignant ones, than mammals^18,19.

BOX 1. -. Transmissible cancers.

While most cancers arise within and die with their host, a handful of transmissible cancers have evolved the ability to spread between individuals and continue proliferation and tumor-formation in new hosts. These cancers challenge the conventional definitions of cancer and provide unique insights into immune evasion strategies and clonal evolution of cancer cells. Though absent in humans and generally rare among vertebrates, three lineages of transmissible cancers are currently known in mammals: two in Tasmanian devils (Sarcophilus harrisii) known as devil facial tumor disease (DFTD1 and DFTD2), and one in domestic dogs (Canis lupus familiaris) known as canine transmissible venereal tumor (CTVT). DFTD cells reversibly suppress MHCI expression via epigenetic modifications of histones, effectively becoming ‘invisible’ to T-cells⁸². Similarly, CTVT cells transiently lose MHCII expression during transmission to avoid immune rejection⁸³. These adaptations parallel findings in human cancers, where MHC loss is a hallmark of immune escape in metastatic and therapy-resistant tumors⁸⁴. Studying transmissible cancers provides a unique perspective to investigate how malignant cells overcome immune barriers, a process critical to understanding metastasis and immunotherapy resistance in human cancers.

What is less clear is whether we consider cancer to exist beyond vertebrates. To address this, we must start with definitions of cancer that encompass the diversity of metazoan body plans, and which can be satisfied by evidence from basic pathology. One simple definition of cancer is an inappropriately proliferating group of cells that grows invasively out of its site of origin. By this criterion, cancer can indeed be found in invertebrates. The most species-rich group of animals on Earth are the insects, which include the fruit fly (Drosophila melanogaster) where both naturally-occurring and experimentally-induced tumors match the aforementioned definition^20–22. Tumors have been documented in other arthropods, as well as mollusks²⁵, corals¹³, and Hydra^23–24, but some of these do not meet all the criteria for the cancer definition provided above (e.g. calicoblastic neoplasms of corals or tumors in general in Hydra lack invasive behavior). Evidence for tumors is lacking in phyla such as echinoderms (e.g. starfishes), nematodes, and sponges, although more systematic studies may reveal the presence of such tumors. Thus, more work is needed to determine the true scope of cancer across the animal kingdom.

Fruit flies, the best-studied host of cancer among invertebrates, highlight issues that arise when considering species less closely related to humans²¹. Fly tumors share many characteristics with human tumors, including uncontrolled division of immortalized cells, defects in differentiation, destruction of the basement membrane, and migration into neighboring tissues. Fly tumors also induce remarkably analogous tumor–host interactions, including the co-option of an oxygen supply, recognition by immune cells, and the ability to induce systemic (paraneoplastic) cachexia and coagulopathy (impaired blood clotting)²⁰. However, unlike human tumors, fly tumors can result from transformation through only one or two genetic insults and are genetically relatively stable; moreover, since insects do not have a vascular circulatory system, whether they metastasize is ambiguous^26,27. Thus, it is important to keep in mind the particular anatomy and lifestyle of the organism under scrutiny when looking for cancer features.

Nevertheless, the basic cellular processes that are corrupted by transformation in human tumors are fundamental to all animal cells. Moreover, the tumor-suppressor genes (e.g. TP53) and proto-oncogenes (e.g. Ras genes) that are frequently mutated in human cancers are highly conserved throughout the metazoan lineage, where they play very similar roles. Combined with the widespread tumors documented throughout animal phylogeny, these data support the idea that a comparative approach can shed light on both the ancient origins of tumor formation and the host response to a tumor.

Evolution of cancer resistance mechanisms

All things being equal, we might expect that the likelihood of accumulating mutations would increase with the number of cells and cell divisions within an organism. Therefore, cancer risk should increase with both body size and lifespan. Nonetheless, the existence of animal species such as whales and elephants that show very low cancer incidence despite lifespans of several centuries or body sizes of up to 100 tons represents a puzzle and highlights that some species have evolved remarkable cancer resistance mechanisms. Following the foundational work by Richard Peto²⁸, this phenomenon has been coined ‘Peto’s paradox’²⁹. Some smaller animals including naked mole rats or multiple species of bats have also evolved remarkably low cancer rates^30,31. While data from the wild are extremely scarce, the exceptional cancer resistance of certain species, both large and small, is widely acknowledged. Molecular or cellular mechanisms contributing to resistance in these animals represent a rich resource for knowledge and inspiration for novel cancer prevention or treatment strategies.

The number of natural cancer resistance mechanisms likely to be found is large, as indicated by the diversity of mechanisms identified to date^31,32 (Fig 1). Some mechanisms are general to a wide range of organisms, including through the elimination of expanded clones by normal tissues via cell competition, apoptosis or anoïkis (apoptosis owing to detachment from the extracellular matrix (ECM)), and stabilizing selection within young healthy tissues to limit selection for oncogenic mutations or epigenetic changes, as well as others^33,34. Other mechanisms are more specific to a single species or a handful of closely related taxa and the primary mechanism can vary from more efficient prevention of cancer (e.g., by early contact inhibition (where cell growth and/or migration is slowed or halted when cells come into contact with other cells) in naked mole rats³¹, extrusion of tumors from healthy tissue³⁵, repression of somatic telomerase activity³⁶ and replicative senescence in large bodied taxa^37,38), to improved detection and elimination of damaged cells (e.g., p53-mediated apoptosis in elephants³⁹, attenuated DNA methyltransferase 1 (DNMT1) activity and subsequent derepression of transposable elements in response to hyperplasia in the blind mole rat⁴⁰, and efficient DNA repair in damaged cells e.g., bowhead whales³²). All these mechanisms can be framed within what should be an obvious first principle - that animals have evolved mechanisms that limit the fitness impacts of rogue somatic evolution. Thus, natural selection at the organismal level has driven natural selection at the somatic level.

Figure. 1. Diverse cancer resistance mechanisms of organisms across the tree of life.

Animals exhibit diverse proposed cancer resistance mechanisms, including DNA protection (e.g. e.g. efficient genotoxic drug efflux mediated by the ATP-binding cassette transporters in bats protects the DNA⁵¹), efficient DNA repair (e.g., high levels of cold-inducible RNA-binding protein (CIRBP) and replication protein A2 (RPA2) are present in bowhead whale fibroblasts and increase the efficiency and fidelity of DNA repair³²), effective elimination of damaged cells (e.g., high rates of p53-mediated apoptosis in response to DNA damage in elephants³⁹), preventing clonal expansion of pre-malignant cells (e.g., naked mole rat fibroblasts secrete extremely high molecular weight hyaluronan acting as signal to CD44 receptors and triggering early contact inhibition⁵²), elimination of over-proliferating pre-malignant cells (e.g. blind mole rat cells express very low levels of DNA methyltransferase 1 that fails to maintain DNA methylation on retrotransposable elements during rapid cell proliferation; derepression of RTEs triggers the formation of cytoplasmic RNA-DNA hybrids, which activate the cGAS-STING pathway and induce concerted cell death⁴⁰), and removal of cancer cells via cell competition (e.g., in fruit flies, genetically fitter cells eliminate neighboring abnormal cells, such as those with mutations or altered polarity, through apoptosis triggered by signaling imbalances, innate immune responses, or mechanical stress⁵³).

Even intensively studied and more traditional cancer resistance mechanisms can benefit from the comparative approach. For instance, the immune system and its associated ‘cancer immunosurveillance’ activity⁴¹ are a current frontier of therapy^42,43. Foundational work in the 1990s in fruit flies led to insights into the origins of immune responses in animals^44,45, and immune elimination of tumors was recently described in D. melanogaster, via both phagocytosis by macrophage-like cells⁴⁶ and a humoral-like response based on antimicrobial peptides⁴⁷. In parallel, it has become increasingly clear that immune-based anticancer mechanisms in mammals involve innate as well as adaptive immunity, providing an important complement to the exclusive focus on adaptive immunity of the original immunosurveillance hypothesis⁴⁸. As research turns towards harnessing innate immune responses to cancer in humans⁴⁹, studying immunological elimination of non-mammalian cancer opens up the possibility of testing hypotheses of conserved mechanisms and exploring informative connections, such as the parallels between immunological responses to cancer and to persistent wounds^20,50.

A combination of complementary methods

From its deep historical roots, the field of comparative oncology has expanded substantially in the last two decades, in at least two ways. First, it has become truly comparative, in the sense that studies today incorporate data on many taxa (Table 1). Second, it has capitalized on cutting-edge approaches and technologies, especially at the genomic level. Consequently, we now exist in an era when comparative oncology can truly flourish.

Table 1. Species-specific cancer rates in non-domestic vertebrates.

A list of publicly available primary databases reporting species-specific cancer rates in non-domestic vertebrates (ordered chronologically). Note that all these cancer risk datasets are based on populations under human care (e.g. zoos) and provide disease risk at the time of death (obtained through necropsy). While these databases were compiled independently, some degree of overlap among the recorded individuals is expected, although the extent remains unknown. Minimum number of individuals per species reflects the minimum number of necropsy reports required to estimate cancer rate.

Dataset	Parameter	Taxonomic coverage	Number of species	Number of inspected individuals	Minimum number of individuals per species
Boddy et al. 202017	Neoplasia prevalence; malignancy prevalence	Mammals	41	869	4
Vincze et al. 202215	Cancer mortality risk	Mammals	191	11840	20
Vincze et al. 202215	Age-standardized incidence of cancer mortality	Mammals	172	11192	20
Compton et al. 202418	Neoplasia prevalence; malignancy prevalence	Amphibians	41	3061	20
Compton et al. 202418	Neoplasia prevalence; malignancy prevalence	Reptiles	71	2693	20
Compton et al. 202418	Neoplasia prevalence; malignancy prevalence	Birds	113	5939	20
Compton et al. 202418	Neoplasia prevalence; malignancy prevalence	Mammals	102	5843	20

The last decade has seen an exponential growth of publicly available databases that allow for cross-species explorations of cancer risk and mechanisms of cancer evasion. Data on cancer prevalence in zoo animals allows for the exploration of life-history, ecological, and phylogenetic risk factors of cancer using computational analysis and modeling. High-quality reference genomes of several hundred species are now available, which serve as a basis for powerful comparative genomic studies³⁹, for instance to study the evolution of tumor suppressor mechanisms, or cancer predisposition in taxa at the level of genes and genetic backgrounds. Comparative transcriptomics⁵⁴ (e.g., to identify key regulatory pathways or biomarkers of cancer and potentially pinpoint therapeutic targets), proteomics (e.g. to identify shared or unique protein signatures of cancer development, progression, or to predict treatment response), and metabolomics (e.g., to identify metabolic alterations or metabolic vulnerabilities in cancer) are also more accessible for multiple species. Moreover, advances in high-precision genome sequencing of individuals have improved estimates of mutation rates across different species and tissues⁵⁵, helping to understand mutational events driving cancer across the tree of life. The advent of ultra-accurate duplex sequencing methods promises to enable the quantification of somatic mutational processes from any cell type in any species^55,56, removing technical barriers that have hitherto prevented their study. Similarly, epigenetic biomarkers of aging based on DNA methylation data can be studied across species⁵⁷, potentially helping to understand how epigenetic alterations shape the aging phenotype and the risk of cancer. Finally, artificial intelligence and machine learning is being applied to determine whether conservation of tumor cell morphology across taxa⁵⁸, which can illuminate shared biology, guide drug development, and improve both diagnosis and therapeutic targeting in humans as well as in model and non-model species. All these approaches benefit from improved molecular phylogenies (using DNA sequences to understand the evolutionary relationships between taxa and to reconstruct their evolutionary history) that now provide a robust framework for comparative studies. Collectively, such advances have strongly elevated the opportunities and impact of comparative oncology, enabling researchers to feasibly study how cancer resistance unfolded over evolutionary time.

Using comparative oncology as a starting point, we can now rationally identify novel model organisms for cancer research and perform species-specific studies with the aim of understanding which molecular or cellular mechanisms shape their cancer resistant phenotypes. The study of such taxa is still in its infancy, with only a handful of non-model organisms having been inspected so far (e.g. naked mole rats, elephants, bowhead whales, bats)^30–32. Along with the plethora of methods listed above, advances in gene editing, including CRISPR-Cas9, can be considered to study and validate candidate cancer resistance mechanisms across species. While making genetically modified elephants or whales presents both technical and ethical challenges, these organisms can be used to discover novel mechanisms of cancer resistance, which can then be modeled in mice and ultimately translated to patients.

Translatability of cross-species studies

Understanding diverse tumor-suppressive mechanisms and variance in cancer predisposition across animals holds more than just intellectual interest. It can lead to the development of new cancer therapies and cancer prevention interventions for patients. Mechanisms and genetic adaptations identified in naturally cancer resistant animals can be mimicked in more cancer-prone species using pharmacological or genetic manipulations. Furthermore, investigating how evolution has fine-tuned tumor-suppressive mechanisms in concert with the natural lifespan and reproductive pattern of various animals could reveal how these mechanisms are shaped by natural selection. Such an understanding could provide the opportunity to design interventions mimicking the effects of natural selection. Below we present several examples where comparative biology has resulted in clinically relevant insights.

Autophagy.

Studies in model organisms have revealed that genetically enhancing autophagy can extend lifespans and reduce or delay cancer incidence^59,60. This suggests that variability in autophagy could contribute to variations in lifespans and cancer patterns across organisms. Can we, then, alter the autophagy pathway in individuals to mimic the evolutionary changes brought about by natural selection? Indeed, evidence already exists to support this concept. Lifestyles that enhance autophagy, such as dietary restriction (or altered nutrient intake without restriction) and exercise, have been shown to reduce cancer incidence⁶¹. Nonetheless, the beneficial effects of autophagy-enhancing strategies may apply primarily to cancer prevention or early intervention, since authophagy can also supports cancer cell survival in established tumors⁸⁵.

High molecular mass hyaluronan.

Naked mole rats are exceptionally long-lived for their size and are very resistant to cancer with only a handful of cancer cases reported after decades of observation⁵². High molecular mass hyaluronan plays an important role in the cancer resistance of naked mole rats by preventing hyperplasia⁵². Remarkably, overexpression in mice of the naked mole rat gene encoding the enzyme involved in hyaluronan synthesis reduced cancer incidence and extended mouse lifespan⁶². This provides proof-of-principle that anticancer mechanisms that evolved in cancer-resistant species can be ‘exported’ into other species even if this will need to be shown with more phylogenetically distant species.

Downregulation of DNMT1 to activate transposable elements.

A second mole-rat species, the blind mole rat, which is phylogenetically distant from the naked mole rat even though it too displays long lifespan and cancer resistance, has evolved low DNMT1 activity, which leads to the rapid activation of transposable elements in hyperplastic cells triggering the activation of the interferon response and elimination of affected cells⁴⁰. Remarkably, DNMT1 inhibitors are already actively used in cancer treatment to induce the death of cancer cells through activation of the interferon response⁶³.

Enhanced p53.

Another example of the translatability of comparative oncology to human medicine relates to the extensive work performed on elephants over the last decade. In 2015, two groups of researchers independently concluded that the high cancer resistance of elephants must be related to their genetic architecture^39,64. These researchers showed that the elephant genome harbors 20 copies of the key tumor suppressor gene, TP53, of which most other animal taxa possess a single copy. This remarkable gene expansion retains one ‘ancestral copy’ similar to the TP53 conserved across the animal phylogeny and at least 19 additional truncated copies of TP53 reinserted into the elephant genome over evolutionary time as retrogenes⁶⁵. TP53 codes for the p53 DNA-binding transcription factor and plays a prominent role in DNA repair and, when repair is not possible, in triggering apoptosis. Selection for multiple copies of this gene could contribute to the increased protection against cancer in elephants, which are large and long-lived, through a more efficient p53-mediated DNA damage response. Although some argue that the TP53 retrogenes appear to be inactive and not under evident selection⁶⁶, recent efforts demonstrate that at least one of these retrogenes can trigger non-transcriptional apoptosis through the mitochondria when expressed in human cancer cells⁶⁷, supporting a functional role and potential selection for tumor suppressor gene amplification as a cancer resistance mechanism. This discovery triggered research into a clinical application to prevent or treat human cancer using the elephant TP53. Initial results have confirmed that transgenic mice expressing elephant TP53 survive longer following carcinogenic exposure⁶⁸.

Enhanced DNA repair.

Organisms can achieve cancer resistance not only through enhanced action of tumor suppressive mechanisms that eliminate the damaged cells, but also by improved genome maintenance. This strategy has recently been described in the bowhead whale, which is very large and perhaps the longest-lived mammal. Compared to other mammals, the bowhead whale shows significantly lower rates of mutations achieved through more efficient and accurate DNA double-strand break repair³². This is likely aided by two proteins present in high levels in bowhead whale cells (cold-inducible RNA-binding protein (CIRBP) and replication protein A2 (RPA2)), which increase the efficiency and fidelity of DNA repair even when overexpressed in human cells.

Inherent challenges of translation

The identification of natural tumor-suppressor mechanisms, such as those listed above, highlight the potential of learning from different species to impact the outcomes of patients with cancer. Moreover, given the diversity of life on Earth, it is highly plausible that numerous other natural anti-cancer mechanisms will be discovered in the near future⁶⁹. Translation of such mechanisms to human medicine should be feasible, especially considering the conserved biological processes common to all animals. While promising opportunities may exist, we must acknowledge the inherent challenges. For instance, natural selection has had a considerable amount of time to balance the tradeoffs associated with alteration to pathways contributing to tumor suppression across species (or in particular species). Such costs of pathway manipulations remain poorly understood and we need to recognize the pleiotropic nature of many genes, pathways and processes. A prominent example is TP53, whose upregulation can lead to premature ageing⁷⁰.

Perspectives and Future Directions

As outlined above, comparative oncology has matured into a well-established research field, with specific questions, rich methods, innovative technologies, and robust results. As a cross-disciplinary group of researchers involved in this domain, we outline below key directions that we envision for the advancement of comparative oncology in the coming years.

Interdisciplinary integration.

A crucial imperative for comparative oncology is to improve the integration between medical oncology, veterinary medicine, evolutionary biology, and ecology. Indeed, a major limitation in the application of knowledge gained from comparative oncology has been that medical doctors often lack a background in evolutionary thinking, while laboratory scientists often have limited knowledge of therapies or lack experience of working with non-model animals. Therefore, the translation of findings in comparative oncology can only be achieved by tight cooperation between these groups. In practical terms, we advocate for three changes. International cancer meetings should devote regular sessions to comparative and evolutionary approaches to cancer. Equally, more conferences of an interdisciplinary nature, bringing all of this expertise together should be organised to trigger cooperation among these teams. Major cancer journals should be open to data-driven and conceptual submissions in comparative oncology (instead of limiting such work to evolutionary biology journals, which are generally not read by clinical oncologists). Finally, educational curricula (beginning as early as undergraduate education and continuing through graduate and professional training) should be restructured to reflect the importance of evolutionary approaches to understanding cancer. We must both provide better background in evolutionary biology to medical trainees and convince students of evolutionary biology and ecology to embrace cancer as their main topic of interest. Ultimately, these changes to disseminate knowledge about comparative oncology will drive the connection to clinical practice.

Comparison of the hallmarks of cancer across taxa.

Until now, comparative oncology has focused, understandably, on assessing cancer risk and/or cancer mortality across taxa. Yet a plethora of new discoveries awaits those who will explore the phylogenetic diversity in mechanisms for each of the hallmarks of cancer (e.g., resistance to cell death, genome instability, deregulation of cell metabolism, and replicative immortality⁷¹). We know very little about the cell biology of neoplasms in non-human animals. Crucially, this line of thought does not assume that these traits co-occur with cancer in all taxa where they are found; for instance, knowing in which taxa and through which mechanisms deregulation of cell metabolism occurs will be informative for understanding the connection between cancer and deregulation of cell metabolism in humans, even if it turns out that some taxa undergo deregulation of cell metabolism without having cancer.

Comparison of cancer-associated traits across taxa.

Following observations on the cross-species diversity in cancer risk, researchers were hoping to reveal the key life-history predictors of tumor prevalence across taxa. While many attempts have been made (by examining the effect of body size, lifespan, reproductive rates and others), and while statistical significance was observed in some cases, the proportion of variance in cross-species cancer prevalence explained by these predictors remains negligible. This highlights that cancer risk is likely influenced by a complex interplay of multiple factors beyond the commonly examined life-history traits, potentially including genetic, immunological, and ecological variables that have yet to be fully understood. An important future direction in comparative oncology will be to establish cancer-associated traits across species (i.e., traits that co-occur with cancer although they have yet to be defined as hallmarks of cancer). For example, microbiome composition has been linked to both cancer risk and responses to cancer therapies in humans and model organisms⁷². But can one find interesting correlations between microbiome composition and/or microbiome disruption and cancer risk and/or mortality across the tree of life? This question should be explored systematically in future research. Interestingly, polymorphic microbiomes have been added as an ‘enabling characteristic’ in Hanahan’s most recent update on the hallmarks of cancer⁷³. Other major examples of cancer-associated traits that could be explored across taxa include biological aging, regenerative capabilities, and the regulation of inflammation.

Improving the search for anti-cancer mechanisms.

More rigorous conceptualizations of anti-cancer mechanisms will be needed to explore their impact on cancer risk and mortality across taxa. One potential classification is based on the stage in cancer progression at which anti-cancer mechanisms act: some may function to prevent the initiation of neoplasms, others to prevent the transformation of a benign neoplasm into a cancer, or prevent a cancer from metastasizing, or even prevent a cancer from causing death. The analysis of each transition depends on distinct data (e.g., prevalence of neoplasia versus cancer mortality) and the mechanisms for preventing each of these transitions are likely to be different. Furthermore, even for already well-recognized anti-cancer mechanisms, much more specific work is needed, particularly comparative studies involving multiple taxa. For example, immunological surveillance is often described as one of the major anti-cancer mechanisms, but the most detailed insights into immune components relevant to cancer (e.g., T-cell subsets, cytokines, checkpoint molecules) derive from human or murine studies. While in humans the role of specific immune components is relatively well understood, far less is known about how these components function across species, and under which evolutionary or ecological conditions they are effective. Future work will certainly generate more precise insights through the development of ‘comparative oncoimmunology’. For instance, do phagocytic cells impact cancer initiation and progression in all metazoans (as they do in many mammals and in some insects)? Other promising examples for study include natural killer (NK) cells (which are widespread across metazoans⁷⁴) and immune components that, like cyclic GMP-AMP synthase (cGAS) for instance, display strong homologies across a wideWhile detailed studies in humans—such as Jerome Galon’s work on immune contexture and the immunoscore—have elucidated the role of specific immune components, far less is known about how these components function across species, and under which evolutionary or ecological conditions they are effective or ineffective. variety of taxa⁷⁵ and are known to play a role in cancer resistance in mammals including humans⁷⁶).

Understanding taxonomic variation in metastatic disease.

How much does the incidence of metastasis vary across species, and what explains that variation? Natural selection may have prevented cancer mortality by preventing the evolution of metastasis. So far, we have very little data on the risk of metastatic disease. We also lack hypotheses about which selective pressures might lead to susceptibility to metastatic disease. Progress will likely require access to full necropsy reports from zoos and wildlife sevices, which is currently difficult but not impossible. If there are species that are prone to malignancy but do not develop metastasis, they may have evolved mechanisms to prevent metastasis. We might also test if the organotropism of metastasis seen in humans is similar or different in non-human animals.

Systematic exploration of the impact of environmental exposures on carcinogenesis.

Cancer prevention, whilst perhaps the ultimate goal, has received considerably less attention than its potential treatment. Environmental stressors and contaminants, including industrial, pharmaceutical or agricultural chemicals, air pollution, radiation or light pollution, markedly contribute to carcinogenesis in humans and animals alike^77–79. Despite growing global concern, substantial amounts of pollutants continue to be released into the environment yearly and many currently banned pollutants will persist in our environment for decades or even centuries⁸⁰. A key obstacle is that too little is known about the impact of most environmental factors, for many reasons including long latency from exposure to cancer development, complex interactions between genetic predisposition and environmental contaminants, multiple and often simultaneous exposures to various contaminants, ethical constraints of performing exposure experiments on human subjects and the difficulty of identifying and controlling all potential confounding effects. By developing systematic comparisons of correlations between cancer incidence and exposure to environmental factors in wild taxa and animals living in anthropogenic environments, such as domestic animals, those living in urbanized areas, zoos or degraded habitats, one might highlight key carcinogenic factors that will elicit the formulation of precise and specific hypotheses that can be tested in the lab. Animals that are particularly susceptible to cancer, as well as animals with shorter lifespans, might act as sentinels for the detection of carcinogens that are not yet apparent in humans. Animal populations that experience unusually high cancer rates could also provide insight into environmental conditions (likely resulting from more recent human activities) that have contributed to these greater cancer rates.

Developing studies on cancer in wildlife.

Cancer surveillance programs for wildlife are scarce and must be encouraged. By comparing cancer in animals in the wild versus those in captivity, we might be able to better distinguish the role of environmental factors from intrinsic cancer susceptibility or resistance in shaping cancer prevalence, which may help to inform human cancer epidemiology. However, collecting data on cancer risk in diverse wild animals, especially those living in their natural habitats, is challenging, including due to the diverse nature of cancer and that small but lethal tumors can often go undetected during necropsies. Moreover, recovering carcasses of wild animals alone is very challenging, especially before decomposition or consumption by scavengers, which would affect their suitability for necropsy⁷⁹. Additionally, disentangling cancer-related mortalities from other sources of more obvious deaths, such as predation or other illnesses triggered by cancer-related health issues, poses further issues. Collaborative endeavors involving oncologists, veterinarians, and researchers from diverse fields are essential to overcome these challenges.

Studying critical transitions in the history of life with respect to cancer incidence.

Clearly the transition from unicellular life to multicellular life was a necessary but perhaps not sufficient condition for the development of cancer⁸¹. It is likely that the presence of cell turnover in adult tissues is a key cancer vulnerability. For many organisms, such as Caenorhabditis elegans for instance, cell proliferation ends with development and the adult body is almost entirely composed of quiescent fully differentiated cells, except for the germline, and such organisms do not develop cancer. What is the relationship across taxa (and across organs) between the presence of adult somatic stem cells and the probability of developing cancer? Is indeterminate growth a risk factor for cancer? What process(es) in mammals make them more susceptible to cancer than other vertebrates?

Comparative genomics and functional validation of putative resistance mechanisms

One of the primary goals of comparative oncology is to discover the mechanisms of cancer resistance that have evolved in non-human species and then translate those discoveries to improved cancer prevention and management in humans. Genomic studies that compare cancer resistant to cancer susceptible species, particularly when closely related, can identify genomic regions that appear to have changed by natural selection independently in multiple cancer resistant species. Those genomic changes are putative molecular mechanisms of cancer resistance that we can then engineer into cell lines⁶⁷ and model organisms to test for cancer resistance phenotypes.

Fostering methodological advances in non-model organisms to advance human cancer research.

Applying and refining state-of-the-art molecular techniques (e.g., single-cell DNA and RNA sequencing, metabolomics, proteomics, epigenetic profiling and CRISPR-Cas9) in cancer-resistant, non-model taxa can provide deeper insights into how specific molecular pathways are regulated in cancer resistant species. While such approaches have already provided some fascinating results in a handful of cancer resistant taxa, applying them at a wide taxonomic scale could help identify conserved pathways of tumor prevention, suppression or elimination across species. Such knowledge might help to uncover universal targets for cancer therapy or prevention.

Conclusion

The advancements and insights gained to date from comparative oncology call for a better integration of this approach into oncological research. With increased attention, continuous collaboration between disciplines, and a stronger commitment from conventional cancer biologists and clinical researchers to explore cancer from a new perspective, comparative oncology can truly reshape the landscape of cancer research and treatment.