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One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design., (©2024 The Authors; Published by the American Association for Cancer Research.)

Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes., (©2024 The Authors; Published by the American Association for Cancer Research.)

The clonal evolution model of cancer was developed in the 1950s-1970s and became central to cancer biology in the twenty-first century, largely through studies of cancer genetics. Although it has proven its worth, its structure has been challenged by observations of phenotypic plasticity, non-genetic forms of inheritance, non-genetic determinants of clone fitness and non-tree-like transmission of genes. There is even confusion about the definition of a clone, which we aim to resolve. The performance and value of the clonal evolution model depends on the empirical extent to which evolutionary processes are involved in cancer, and on its theoretical ability to account for those evolutionary processes. Here, we identify limits in the theoretical performance of the clonal evolution model and provide solutions to overcome those limits. Although we do not claim that clonal evolution can explain everything about cancer, we show how many of the complexities that have been identified in the dynamics of cancer can be integrated into the model to improve our current understanding of cancer., (© 2024. Springer Nature Limited.)

Background and Objectives: Cancer develops across nearly every species. However, cancer occurs at unexpected and widely different rates throughout the animal kingdom. The reason for this variation in cancer susceptibility remains an area of intense investigation. Cancer evolves in part through the accumulation of mutations, and therefore, we hypothesized that germline mutation rates would be associated with cancer prevalence and mortality across species., Methodology: We collected previously published data on germline mutation rate and cancer mortality data for 37 vertebrate species., Results: Germline mutation rate was positively correlated with cancer mortality (P-value = 0.0008; R2 = 0.13). Controlling for species' average parental age, maximum longevity, adult body mass or domestication did not improve the model fit (the change (Δ) in Akaike Information Criterion (AIC) was less than 2). However, this model fit was better than a model controlling for species trophic level (ΔAIC > 2)., Conclusions and Implications: The increased death rate from cancer in animals with increased germline mutation rates may suggest underlying hereditary cancer predisposition syndromes similar to those diagnosed in human patients. Species with higher germline mutation rates may benefit from close monitoring for tumors due to increased genetic risk for cancer development. Early diagnoses of cancer in these species may increase their chances of overall survival, especially for threatened and endangered species., Competing Interests: J.D.S. is a co-founder and shareholder employed by Peel Therapeutics, Inc., and L.M.A. is a shareholder and consultant to Peel Therapeutics, Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Progression from pre-cancers like ductal carcinoma in situ (DCIS) to invasive disease (cancer) is driven by somatic evolution and is altered by clinical interventions. We hypothesized that genetic and/or phenotypic intra-tumor heterogeneity would predict clinical outcomes for DCIS since it serves as the substrate for natural selection among cells. We profiled two samples from two geographically distinct foci from each DCIS in both cross-sectional (N = 119) and longitudinal cohorts (N = 224), with whole exome sequencing, low-pass whole genome sequencing, and a panel of immunohistochemical markers. In the longitudinal cohorts, the only statistically significant predictors of time to non-invasive DCIS recurrence were the combination of treatment (lumpectomy only vs mastectomy or lumpectomy with radiation, HR = 12.13, p = 0.003, Wald test with FDR correction), ER status (HR = 0.16 for ER+ compared to ER-, p = 0.0045), and divergence in SNVs between the two samples (HR = 1.33 per 10% divergence, p = 0.018). SNV divergence also distinguished between pure DCIS and DCIS synchronous with invasive disease in the cross-sectional cohort. In contrast, the only statistically significant predictors of time to progression to invasive disease were the combination of the width of the surgical margin (HR = 0.67 per mm, p = 0.043) and the number of mutations that were detectable at high allele frequencies (HR = 1.30 per 10 SNVs, p = 0.02). These results imply that recurrence with DCIS is a clinical and biological process different from invasive progression., Competing Interests: Conflict of Interest Statement: The authors declare no potential conflicts of interest

Background and Objectives: Cancer is a disease that affects nearly all multicellular life, including the broad and diverse taxa of Aves. While little is known about the factors that contribute to cancer risk across Aves, life history trade-offs may explain some of this variability in cancer prevalence. We predict birds with high investment in reproduction may have a higher likelihood of developing cancer. In this study, we tested whether life history traits are associated with cancer prevalence in 108 species of birds., Methodology: We obtained life history data from published databases and cancer data from 5,729 necropsies from 108 species of birds across 24 taxonomic orders from 25 different zoological facilities. We performed phylogenetically controlled regression analyses between adult body mass, lifespan, incubation length, clutch size, sexually dimorphic traits, and both neoplasia and malignancy prevalence. We also compared the neoplasia and malignancy prevalence of female and male birds., Results: Providing support for a life history trade-off between somatic maintenance and reproduction, we found a positive relationship between clutch size and cancer prevalence across Aves. There was no significant association with body mass, lifespan, incubation length, sexual dimorphism, and cancer., Conclusions and Implications: Life history theory presents an important framework for understanding differences in cancer defenses across various species. These results suggest a trade-off between reproduction and somatic maintenance, where Aves with small clutch sizes get less cancer., Competing Interests: We declare we do not have any conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Cells in obligately multicellular organisms by definition have aligned fitness interests, minimum conflict, and cannot reproduce independently. However, some cells eat other cells within the same body, sometimes called cell cannibalism. Such cell-in-cell events have not been thoroughly discussed in the framework of major transitions to multicellularity. We performed a systematic screening of 508 articles, from which we chose 115 relevant articles in a search for cell-in-cell events across the tree of life, the age of cell-in-cell-related genes, and whether cell-in-cell events are associated with normal multicellular development or cancer. Cell-in-cell events are found across the tree of life, from some unicellular to many multicellular organisms, including non-neoplastic and neoplastic tissue. Additionally, out of the 38 cell-in-cell-related genes found in the literature, 14 genes were over 2.2 billion years old, i.e., older than the common ancestor of some facultatively multicellular taxa. All of this suggests that cell-in-cell events may have originated before the origins of obligate multicellularity. Thus, our results show that cell-in-cell events exist in obligate multicellular organisms, but are not a defining feature of them. The idea of eradicating cell-in-cell events from obligate multicellular organisms as a way of treating cancer, without considering that cell-in-cell events are also part of normal development, should be abandoned., (© 2024. The Author(s).)

Adaptive therapy, an ecologically inspired approach to cancer treatment, aims to overcome resistance and reduce toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life instead of killing the maximum number of cancer cells. In preparation for a clinical trial, we used endocrine-resistant MCF7 breast cancer to stimulate second-line therapy and tested adaptive therapy using capecitabine, gemcitabine, or their combination in a mouse xenograft model. Dose modulation adaptive therapy with capecitabine alone increased survival time relative to MTD but not statistically significantly (HR = 0.22, 95% CI = 0.043-1.1, p = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI = 0.024-0.55, p = 0.007) and intermittent adaptive therapies, the survival time was significantly increased compared to high-dose combination therapy (HR = 0.07, 95% CI = 0.013-0.42, p = 0.003). Overall, the survival time increased with reduced dose for both single drugs ( p < 0.01) and combined drugs ( p < 0.001), resulting in tumors with fewer proliferation cells ( p = 0.0026) and more apoptotic cells ( p = 0.045) compared to high-dose therapy. Adaptive therapy favors slower-growing tumors and shows promise in two-drug alternating regimens instead of being combined.

Hershey and colleagues recently showed how clones in a triple-negative breast cancer cell line cooperate for their mutual fitness benefit. In this system, clones exchange soluble metabolites to increase their in vitro growth rate at low population densities, therefore mitigating the documented growth barrier that reduces individual fitness in small tumor cell populations (Allee effect). Such cooperation could aid important transitions in cancer progression in which cancer cell populations are small, like invasion or metastasis. Using orthotopic transplantation, the authors demonstrate that this cooperation is functional in one such transition in vivo, increasing the metastatic load and number of metastases, which are usually polyclonal. Together, these findings highlight the need to consider ecologic interactions to properly understand tumor growth dynamics, and how they complement the standing evolutionary model of cancer progression in our quest to understand and treat cancer., (©2023 American Association for Cancer Research.)

The mouse is a widely used model organism in cancer research. However, no computational methods exist to identify cancer driver genes in mice due to a lack of labeled training data. To address this knowledge gap, we adapted the GUST (Genes Under Selection in Tumors) model, originally trained on human exomes, to mouse exomes via transfer learning. The resulting tool, called GUST-mouse, can estimate long-term and short-term evolutionary selection in mouse tumors, and distinguish between oncogenes, tumor suppressor genes, and passenger genes using high-throughput sequencing data. We applied GUST-mouse to analyze 65 exomes of mouse primary breast cancer models and 17 exomes of mouse leukemia models. Comparing the predictions between cancer types and between human and mouse tumors revealed common and unique driver genes. The GUST-mouse method is available as an open-source R package on github.

Chimerism is a widespread phenomenon across the tree of life. It is defined as a multicellular organism composed of cells from other genetically distinct entities. This ability to 'tolerate' non-self cells may be linked to susceptibility to diseases like cancer. Here we test whether chimerism is associated with cancers across obligately multicellular organisms in the tree of life. We classified 12 obligately multicellular taxa from lowest to highest chimerism levels based on the existing literature on the presence of chimerism in these species. We then tested for associations of chimerism with tumour invasiveness, neoplasia (benign or malignant) prevalence and malignancy prevalence in 11 terrestrial mammalian species. We found that taxa with higher levels of chimerism have higher tumour invasiveness, though there was no association between malignancy or neoplasia and chimerism among mammals. This suggests that there may be an important biological relationship between chimerism and susceptibility to tissue invasion by cancerous cells. Studying chimerism might help us identify mechanisms underlying invasive cancers and also could provide insights into the detection and management of emerging transmissible cancers., Competing Interests: We declare we do not have conflicts of interest., (Copyright: © 2023 Kapsetaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cancers occur across species. Understanding what is consistent and varies across species can provide new insights into cancer initiation and evolution, with significant implications for animal welfare and wildlife conservation. We build a pan-species cancer digital pathology atlas (panspecies.ai) and conduct a pan-species study of computational comparative pathology using a supervised convolutional neural network algorithm trained on human samples. The artificial intelligence algorithm achieves high accuracy in measuring immune response through single-cell classification for two transmissible cancers (canine transmissible venereal tumour, 0.94; Tasmanian devil facial tumour disease, 0.88). In 18 other vertebrate species (mammalia = 11, reptilia = 4, aves = 2, and amphibia = 1), accuracy (range 0.57-0.94) is influenced by cell morphological similarity preserved across different taxonomic groups, tumour sites, and variations in the immune compartment. Furthermore, a spatial immune score based on artificial intelligence and spatial statistics is associated with prognosis in canine melanoma and prostate tumours. A metric, named morphospace overlap, is developed to guide veterinary pathologists towards rational deployment of this technology on new samples. This study provides the foundation and guidelines for transferring artificial intelligence technologies to veterinary pathology based on understanding of morphological conservation, which could vastly accelerate developments in veterinary medicine and comparative oncology., (© 2023. The Author(s).)

Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer 1-6 . At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection., (© 2023. The Author(s).)

Approximately 20 TP53 retrogenes exist in the African and Asian elephant genomes (Loxodonta Africana, Elephas Maximus) in addition to a conserved TP53 gene that encodes a full-length protein. Elephant TP53-RETROGENE 9 (TP53-R9) encodes a p53 protein (p53-R9) that is truncated in the middle of the canonical DNA binding domain. This C-terminally truncated p53 retrogene protein lacks the nuclear localization signals and oligomerization domain of its full-length counterpart. When expressed in human osteosarcoma cells (U2OS), p53-R9 binds to Tid1, the chaperone protein responsible for mitochondrial translocation of human p53 in response to cellular stress. Tid1 expression is required for p53-R9-induced apoptosis. At the mitochondria, p53-R9 binds to the pro-apoptotic BCL-2 family member Bax, which leads to caspase activation, cytochrome c release, and cell death. Our data show, for the first time, that expression of this truncated elephant p53 retrogene protein induces apoptosis in human cancer cells. Understanding the molecular mechanism by which the additional elephant TP53 retrogenes function may provide evolutionary insight that can be utilized for the development of therapeutics to treat human cancers., (© 2023. The Author(s).)

Purpose of Review: Cancers are a leading cause of death in humans and for many other species. Diet has often been associated with cancers, and the microbiome is an essential mediator between diet and cancers. Here, we review the work on cancer and the microbiome across species to search for broad patterns of susceptibility associated with different microbial species., Recent Findings: Some microbes, such as Helicobacter bacteria, papillomaviruses, and the carnivore-associated Fusobacteria, consistently induce tumorigenesis in humans and other species. Other microbes, such as the milk-associated Lactobacillus, consistently inhibit tumorigenesis in humans and other species. We systematically reviewed over a thousand published articles and identified links between diet, microbes, and cancers in several species of mammals, birds, and flies. Future work should examine a larger variety of host species to discover new model organisms for human preclinical trials, to better understand the observed variance in cancer prevalence across species, and to discover which microbes and diets are associated with cancers across species. Ultimately, this could help identify microbial and dietary interventions to diagnose, prevent, and treat cancers in humans as well as other animals., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers., (© 2022. The Author(s).)

The standard of care for cancer patients aims to eradicate the tumor by killing the maximum number of cancer cells using the maximum tolerated dose (MTD) of a drug. MTD causes significant toxicity and selects for resistant cells, eventually making the tumor refractory to treatment. Adaptive therapy aims to maximize time to progression (TTP), by maintaining sensitive cells to compete with resistant cells. We explored both dose modulation (DM) protocols and fixed dose (FD) interspersed with drug holiday protocols. In contrast to previous single drug protocols, we explored the determinants of success of two-drug adaptive therapy protocols, using an agent-based model. In almost all cases, DM protocols (but not FD protocols) increased TTP relative to MTD. DM protocols worked well when there was more competition, with a higher cost of resistance, greater cell turnover, and when crowded proliferating cells could replace their neighbors. The amount that the drug dose was changed, mattered less. The more sensitive the protocol was to tumor burden changes, the better. In general, protocols that used as little drug as possible, worked best. Preclinical experiments should test these predictions, especially dose modulation protocols, with the goal of generating successful clinical trials for greater cancer control.

In mammography, calcifications are one of the most common signs of breast cancer. Detection of such lesions is an active area of research for computer-aided diagnosis and machine learning algorithms. Due to limited numbers of positive cases, many supervised detection models suffer from overfitting and fail to generalize. We present a one-class, semi-supervised framework using a deep convolutional autoencoder trained with over 50,000 images from 11,000 negative-only cases. Since the model learned from only normal breast parenchymal features, calcifications produced large signals when comparing the residuals between input and reconstruction output images. As a key advancement, a structural dissimilarity index was used to suppress non-structural noises. Our selected model achieved pixel-based AUROC of 0.959 and AUPRC of 0.676 during validation, where calcification masks were defined in a semi-automated process. Although not trained directly on any cancers, detection performance of calcification lesions on 1,883 testing images (645 malignant and 1238 negative) achieved 75% sensitivity at 2.5 false positives per image. Performance plateaued early when trained with only a fraction of the cases, and greater model complexity or a larger dataset did not improve performance. This study demonstrates the potential of this anomaly detection approach to detect mammographic calcifications in a semi-supervised manner with efficient use of a small number of labeled images, and may facilitate new clinical applications such as computer-aided triage and quality improvement.

While the genomes of normal tissues undergo dynamic changes over time, little is understood about the temporal-spatial dynamics of genomes in premalignant tissues that progress to cancer compared to those that remain cancer-free. Here we use whole genome sequencing to contrast genomic alterations in 427 longitudinal samples from 40 patients with stable Barrett's esophagus compared to 40 Barrett's patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes are active in Barrett's tissue regardless of outcome, with high levels of mutation, ESAD gene and focal chromosomal alterations, and similar mutational signatures. The critical distinction between stable Barrett's versus those who progress to cancer is acquisition and expansion of TP53-/- cell populations having complex structural variants and high-level amplifications, which are detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett's esophagus and define key genomic features specific to progression to esophageal adenocarcinoma, both of which are critical for cancer prevention and early detection strategies., (© 2022. The Author(s).)

Background Improving diagnosis of ductal carcinoma in situ (DCIS) before surgery is important in choosing optimal patient management strategies. However, patients may harbor occult invasive disease not detected until definitive surgery. Purpose To assess the performance and clinical utility of mammographic radiomic features in the prediction of occult invasive cancer among women diagnosed with DCIS on the basis of core biopsy findings. Materials and Methods In this Health Insurance Portability and Accountability Act-compliant retrospective study, digital magnification mammographic images were collected from women who underwent breast core-needle biopsy for calcifications that was performed at a single institution between September 2008 and April 2017 and yielded a diagnosis of DCIS. The database query was directed at asymptomatic women with calcifications without a mass, architectural distortion, asymmetric density, or palpable disease. Logistic regression with regularization was used. Differences across training and internal test set by upstaging rate, age, lesion size, and estrogen and progesterone receptor status were assessed by using the Kruskal-Wallis or χ 2 test. Results The study consisted of 700 women with DCIS (age range, 40-89 years; mean age, 59 years ± 10 [standard deviation]), including 114 with lesions (16.3%) upstaged to invasive cancer at subsequent surgery. The sample was split randomly into 400 women for the training set and 300 for the testing set (mean ages: training set, 59 years ± 10; test set, 59 years ± 10; P = .85). A total of 109 radiomic and four clinical features were extracted. The best model on the test set by using all radiomic and clinical features helped predict upstaging with an area under the receiver operating characteristic curve of 0.71 (95% CI: 0.62, 0.79). For a fixed high sensitivity (90%), the model yielded a specificity of 22%, a negative predictive value of 92%, and an odds ratio of 2.4 (95% CI: 1.8, 3.2). High specificity (90%) corresponded to a sensitivity of 37%, positive predictive value of 41%, and odds ratio of 5.0 (95% CI: 2.8, 9.0). Conclusion Machine learning models that use radiomic features applied to mammographic calcifications may help predict upstaging of ductal carcinoma in situ, which can refine clinical decision making and treatment planning. © RSNA, 2022.

Does asking students to apply concepts from evolution to a fictional context, compared to a novel biological context, improve their understanding, exam performance or enjoyment of the material? Or does it harm their education by taking time away from true biology? At our institution, we sometimes ask students to apply life history theory to species from fictional movies, television shows or books. Previously, we had used a factual article on life history theory, to supplement our textbook. We wrote an alternative introduction to life history theory (included in the additional files for educational use), using Tolkien's fictional species from his Lord of the Rings books. We also introduce the biological species definition, sexual selection, sexual dimorphism, kin selection, and the handicap principle, as those concepts arose naturally in the discussion of the fictional species. Life history theory predicts strong correlations between traits affecting reproduction, growth and survival, which are all shaped by the ecology of the species. Thus, we can teach life history theory by asking students to infer traits and aspects of the ecology of a fictional species that have never been described, based on the partial information included in the fictional sources. In a large, third year undergraduate evolution course at Arizona State University, we randomized 16 tutorial sections of a total of 264 students to either read our article on the life history theory of Lord of the Rings, or the factual article we had used previously in the course. We found that the exam performance on life history questions for the two groups were almost identical, except that fans of The Lord of the Rings who had read our article did better on the exam. Enjoyment, engagement and interest in life history theory was approximately a full point higher on a 5-point Likert scale for the students that had read the fictional article, and was highly statistically significantly different (T-test p  < 0.001 for all questions). There was no difference between the two groups in their familiarity or enjoyment of The Lord of the Rings stories themselves. Reading the article that taught life history theory by applying it to the species of The Lord of the Rings neither helped nor harmed exam performance, but did significantly improve student enjoyment, engagement and interest in life history theory, and even improved exam scores in students who liked The Lord of the Rings. Using fiction to teach science may also help to engage non-traditional students, such as world-builders, outside of our institutions of education. By encouraging students to apply the scientific ideas to their favorite stories from their own cultures, we may be able to improve both inclusivity and education., Supplementary Information: The online version contains supplementary material available at 10.1186/s12052-022-00160-8., Competing Interests: Competing interestsThe authors have no competing interests with this work., (© The Author(s) 2022.)

Cancer is a ubiquitous disease of metazoans, predicted to disproportionately affect larger, long-lived organisms owing to their greater number of cell divisions, and thus increased probability of somatic mutations 1,2 . While elevated cancer risk with larger body size and/or longevity has been documented within species 3-5 , Peto's paradox indicates the apparent lack of such an association among taxa 6 . Yet, unequivocal empirical evidence for Peto's paradox is lacking, stemming from the difficulty of estimating cancer risk in non-model species. Here we build and analyse a database on cancer-related mortality using data on adult zoo mammals (110,148 individuals, 191 species) and map age-controlled cancer mortality to the mammalian tree of life. We demonstrate the universality and high frequency of oncogenic phenomena in mammals and reveal substantial differences in cancer mortality across major mammalian orders. We show that the phylogenetic distribution of cancer mortality is associated with diet, with carnivorous mammals (especially mammal-consuming ones) facing the highest cancer-related mortality. Moreover, we provide unequivocal evidence for the body size and longevity components of Peto's paradox by showing that cancer mortality risk is largely independent of both body mass and adult life expectancy across species. These results highlight the key role of life-history evolution in shaping cancer resistance and provide major advancements in the quest for natural anticancer defences., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Trichoplax adhaerens is the simplest multicellular animal with tissue differentiation and somatic cell turnover. Like all other multicellular organisms, it should be vulnerable to cancer, yet there have been no reports of cancer in T. adhaerens or any other placozoan. We investigated the cancer resistance of T. adhaerens, discovering that they are able to tolerate high levels of radiation damage (218.6 Gy). To investigate how T. adhaerens survive levels of radiation that are lethal to other animals, we examined gene expression after the X-ray exposure, finding overexpression of genes involved in DNA repair and apoptosis including the MDM2 gene. We also discovered that T. adhaerens extrudes clusters of inviable cells after X-ray exposure. T. adhaerens is a valuable model organism for studying the molecular, genetic, and tissue-level mechanisms underlying cancer suppression., Competing Interests: The authors have declared that no competing interests exist.

Most tissue collections of neoplasms are composed of formalin-fixed and paraffin-embedded (FFPE) excised tumor samples used for routine diagnostics. DNA sequencing is becoming increasingly important in cancer research and clinical management; however it is difficult to accurately sequence DNA from FFPE samples. We developed and validated a new bioinformatic pipeline to use existing variant-calling strategies to robustly identify somatic single nucleotide variants (SNVs) from whole exome sequencing using small amounts of DNA extracted from archival FFPE samples of breast cancers. We optimized this strategy using 28 pairs of technical replicates. After optimization, the mean similarity between replicates increased 5-fold, reaching 88% (range 0-100%), with a mean of 21.4 SNVs (range 1-68) per sample, representing a markedly superior performance to existing tools. We found that the SNV-identification accuracy declined when there was less than 40 ng of DNA available and that insertion-deletion variant calls are less reliable than single base substitutions. As the first application of the new algorithm, we compared samples of ductal carcinoma in situ of the breast to their adjacent invasive ductal carcinoma samples. We observed an increased number of mutations (paired-samples sign test, P < 0.05), and a higher genetic divergence in the invasive samples (paired-samples sign test, P < 0.01). Our method provides a significant improvement in detecting SNVs in FFPE samples over previous approaches., (© The Author(s) 2021. Published by Oxford University Press.)

Disease susceptibility and resistance are important factors for the conservation of endangered species, including elephants. We analyzed pathology data from 26 zoos and report that Asian elephants have increased neoplasia and malignancy prevalence compared with African bush elephants. This is consistent with observed higher susceptibility to tuberculosis and elephant endotheliotropic herpesvirus (EEHV) in Asian elephants. To investigate genetic mechanisms underlying disease resistance, including differential responses between species, among other elephant traits, we sequenced multiple elephant genomes. We report a draft assembly for an Asian elephant, and defined 862 and 1,017 conserved potential regulatory elements in Asian and African bush elephants, respectively. In the genomes of both elephant species, conserved elements were significantly enriched with genes differentially expressed between the species. In Asian elephants, these putative regulatory regions were involved in immunity pathways including tumor-necrosis factor, which plays an important role in EEHV response. Genomic sequences of African bush, forest, and Asian elephant genomes revealed extensive sequence conservation at TP53 retrogene loci across three species, which may be related to TP53 functionality in elephant cancer resistance. Positive selection scans revealed outlier genes related to additional elephant traits. Our study suggests that gene regulation plays an important role in the differential inflammatory response of Asian and African elephants, leading to increased infectious disease and cancer susceptibility in Asian elephants. These genomic discoveries can inform future functional and translational studies aimed at identifying effective treatment approaches for ill elephants, which may improve conservation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

The application of evolutionary and ecological principles to cancer prevention and treatment, as well as recognizing cancer as a selection force in nature, has gained impetus over the last 50 years. Following the initial theoretical approaches that combined knowledge from interdisciplinary fields, it became clear that using the eco-evolutionary framework is of key importance to understand cancer. We are now at a pivotal point where accumulating evidence starts to steer the future directions of the discipline and allows us to underpin the key challenges that remain to be addressed. Here, we aim to assess current advancements in the field and to suggest future directions for research. First, we summarize cancer research areas that, so far, have assimilated ecological and evolutionary principles into their approaches and illustrate their key importance. Then, we assembled 33 experts and identified 84 key questions, organized around nine major themes, to pave the foundations for research to come. We highlight the urgent need for broadening the portfolio of research directions to stimulate novel approaches at the interface of oncology and ecological and evolutionary sciences. We conclude that progressive and efficient cross-disciplinary collaborations that draw on the expertise of the fields of ecology, evolution and cancer are essential in order to efficiently address current and future questions about cancer., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Cancer is caused by genetic alterations that affect cellular fitness, and multicellular organisms have evolved mechanisms to suppress cancer such as cell cycle checkpoints and apoptosis. These pathways may be enhanced by the addition of tumor suppressor gene paralogs or deletion of oncogenes. To provide insights to the evolution of cancer suppression across the mammalian radiation, we estimated copy numbers for 548 human tumor suppressor gene and oncogene homologs in 63 mammalian genome assemblies. The naked mole rat contained the most cancer gene copies, consistent with the extremely low rates of cancer found in this species. We found a positive correlation between a species' cancer gene copy number and its longevity, but not body size, contrary to predictions from Peto's Paradox. Extremely long-lived mammals also contained more copies of caretaker genes in their genomes, suggesting that the maintenance of genome integrity is an essential form of cancer prevention in long-lived species. We found the strongest association between longevity and copy numbers of genes that are both germline and somatic tumor suppressor genes, suggesting that selection has acted to suppress both hereditary and sporadic cancers. We also found a strong relationship between the number of tumor suppressor genes and the number of oncogenes in mammalian genomes, suggesting that complex regulatory networks mediate the balance between cell proliferation and checks on tumor progression. This study is the first to investigate cancer gene expansions across the mammalian radiation and provides a springboard for potential human therapies based on evolutionary medicine., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Beneficial mutations that arise in an evolving asexual population may compete or interact in ways that alter the overall rate of adaptation through mechanisms such as clonal or functional interference. The application of multiple selective pressures simultaneously may allow for a greater number of adaptive mutations, increasing the opportunities for competition between selectively advantageous alterations, and thereby reducing the rate of adaptation. We evolved a strain of Saccharomyces cerevisiae that could not produce its own histidine or uracil for ~500 generations under one or three selective pressures: limitation of the concentration of glucose, histidine, and/or uracil in the media. The rate of adaptation was obtained by measuring evolved relative fitness using competition assays. Populations evolved under a single selective pressure showed a statistically significant increase in fitness on those pressures relative to the ancestral strain, but the populations evolved on all three pressures did not show a statistically significant increase in fitness over the ancestral strain on any single pressure. Simultaneously limiting three essential nutrients for a population of S. cerevisiae effectively slows the rate of evolution on any one of the three selective pressures applied, relative to the single selective pressure cases. We identify possible mechanisms for fitness changes seen between populations evolved on one or three limiting nutrient pressures by high-throughput sequencing. Adding multiple selective pressures to evolving disease like cancer and infectious diseases could reduce the rate of adaptation and thereby may slow disease progression, prolong drug efficacy and prevent deaths., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Carcinogenesis is a process of somatic evolution. Previous models of stem and transient amplifying cells in epithelial proliferating units like colonic crypts showed that intermediate numbers of stem cells in a crypt should optimally prevent progression to cancer. If a stem cell population is too small, it is easy for a mutator mutation to drift to fixation. If it is too large, it is easy for selection to drive cell fitness enhancing carcinogenic mutations to fixation. Here, we show that a multiscale microsimulation, that captures both within-crypt and between-crypt evolutionary dynamics, leads to a different conclusion. Epithelial tissues are metapopulations of crypts. We measured time to initiation of a neoplasm, implemented as inactivation of both alleles of a tumor suppressor gene. In our model, time to initiation is dependent on the spread of mutator clones in the crypts. The proportion of selectively beneficial and deleterious mutations in somatic cells is unknown and so was explored with a parameter. When the majority of non-neutral mutations are deleterious, the fitness of mutator clones tends to decline. When crypts are maintained by few stem cells, intercrypt competition tends to remove crypts with fixed mutators. When there are many stem cells within a crypt, there is virtually no crypt turnover, but mutator clones are suppressed by within-crypt competition. If the majority of non-neutral mutations are beneficial to the clone, then these results are reversed and intermediate-sized crypts provide the most protection against initiation. These results highlight the need to understand the dynamics of turnover and the mechanisms that control homeostasis, both at the level of stem cells within proliferative units and at the tissue level of competing proliferative units. Determining the distribution of fitness effects of somatic mutations will also be crucial to understanding the dynamics of tumor initiation and progression., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Objective: The goal of this study is to use adjunctive classes to improve a predictive model whose performance is limited by the common problems of small numbers of primary cases, high feature dimensionality, and poor class separability. Specifically, our clinical task is to use mammographic features to predict whether ductal carcinoma in situ (DCIS) identified at needle core biopsy will be later upstaged or shown to contain invasive breast cancer., Methods: To improve the prediction of pure DCIS (negative) versus upstaged DCIS (positive) cases, this study considers the adjunctive roles of two related classes: atypical ductal hyperplasia (ADH), a non-cancer type of breast abnormity, and invasive ductal carcinoma (IDC), with 113 computer vision based mammographic features extracted from each case. To improve the baseline Model A's classification of pure vs. upstaged DCIS, we designed three different strategies (Models B, C, D) with different ways of embedding features or inputs., Results: Based on ROC analysis, the baseline Model A performed with AUC of 0.614 (95% CI, 0.496-0.733). All three new models performed better than the baseline, with domain adaptation (Model D) performing the best with an AUC of 0.697 (95% CI, 0.595-0.797)., Conclusion: We improved the prediction performance of DCIS upstaging by embedding two related pathology classes in different training phases., Significance: The three new strategies of embedding related class data all outperformed the baseline model, thus demonstrating not only feature similarities among these different classes, but also the potential for improving classification by using other related classes.

Background: Cancer is a common diagnosis in many mammalian species, yet they vary in their vulnerability to cancer. The factors driving this variation are unknown, but life history theory offers potential explanations to why cancer defense mechanisms are not equal across species., Methodology: Here we report the prevalence of neoplasia and malignancy in 37 mammalian species, representing 11 mammalian orders, using 42 years of well curated necropsy data from the San Diego Zoo and San Diego Zoo Safari Park. We collected data on life history components of these species and tested for associations between life history traits and both neoplasia and malignancy, while controlling for phylogenetic history., Results: These results support Peto's paradox, in that we find no association between lifespan and/or body mass and the prevalence of neoplasia or malignancy. However, a positive relationship exists between litter size and prevalence of malignancy (P = 0.005, Adj. R2 = 0.212), suggesting that a species' life history strategy may influence cancer vulnerabilities. Lastly, we tested for the relationship between placental invasiveness and malignancy. We find no evidence for an association between placental depth and malignancy prevalence (P = 0.618, Adj. R2 = 0.068)., Conclusions: Life history theory offers a powerful framework to understand variation in cancer defenses across the tree of life. These findings provide insight into the relationship between life history traits and cancer vulnerabilities, which suggest a trade-off between reproduction and cancer defenses., Lay Summary: Why are some mammals more vulnerable to cancer than others? We test whether life history trade-offs may explain this variation in cancer risk. Bigger, longer-lived animals do not develop more cancer compared to smaller, shorter-lived animals. However, we find a positive association between litter size and cancer prevalence in mammals., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 10 8 -10 9 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance.