A multi-scale approach of ecological and evolutionary processes involved in cancer

Le cancer est une pathologie caractérisée par la transformation de cellules de l'organisme, et leur prolifération incontrôlée aux dépens de l'organisme. Elle peut toucher tout tissu de l'organisme, et menacer la survie des patients à terme. Ce phénomène est souvent interprété comme une dégénérescence de l'organisme au cours du vieillissement, mais ce paradigme ne suffit pas à embrasser toute la complexité de cette maladie. En effet, la progression cancéreuse est basée sur des mutations qui nourrissent une prolifération différentielle des cellules, et elle peut donc être décrite par une dynamique écologique et évolutive. En outre, les manifestations du cancer sont extrêmement répandues dans tout le vivant, et peuvent être attribuées à l'émergence des organismes multicellulaires il y a un milliard d'années. Le cancer a donc toujours représenté une contrainte sur l'évolution des organismes. La compréhension globale du cancer nécessite donc d'élucider comment les dynamiques éco-évolutives intra- et inter-organisme s'influencent mutuellement au cours des temps évolutifs. A l'aide de conceptualisation et d'approches théoriques, nous montrons qu'une approche multi-échelle offre de nouvelles perspectives sur les processus écologiques et évolutifs impliqués dans le cancer. A l'échelle intra-tumorale, nous nous concentrons sur les interactions entre cellules cancéreuses et au rôle structurant que ces interactions peuvent avoir dans les écosystèmes tumoraux. Nous montrons notamment que la fréquence des interactions diminue la diversité clonale durant l'expansion tumorale. A l'échelle populationnelle, nous formulons et explorons une hypothèse sur l'origine de la forte fréquence des cancers héréditaires : les défenses anti-cancer sélectionnées dans les environnements cancérogènes pourraient compenser la progression cancéreuse, et donc autoriser la persistance d'allèles pro-oncogéniques à l'équilibre mutation-dérive. Nous considérons enfin les interactions réciproques entre évolution des organismes et évolution des cellules cancéreuses : spécifiquement l'évolution emboîtée de la résistance et de la tolérance au cancer, et l'évolution de stratégies de manipulation de l'hôte chez les cellules cancéreuses. Nous montrons notamment que l'évolution intra-individuelle favorise la tolérance, tandis que l'évolution inter-individuelle favorise la résistance.Cancer is a pathology characterized by organism cell transformation and uncontrolled cell proliferation at the expense of the organism. It can affect any tissue in the organism, and can eventually threaten patient survival. This phenomenon is commonly viewed as the result of organism decay during ageing, yet this paradigm fails to embrace the whole complexity of this disease. Cancer progression indeed relies on mutations which fuel differential cell proliferation, and thus it can be described by ecological and evolutionary dynamics. Besides, cancer manifestations are widespread across living organisms, and may be due to the emergence of multicellularity a billion years ago. Cancer has thus always constrained the evolution of organisms. How intra- and inter-organism eco-evolutionary dynamics influence each other across evolutionary times must be investigated to fully understand cancer. Through conceptualization and theoretical approaches, we show that a multi-scale approach offers novel prospects on ecological and evolutionary processes involved in cancer. At intratumor scale, we focus on interactions between cancer cells and on how these interactions structure tumor ecosystems. We notably find that frequent interactions yields lower clonal diversity during tumor expansion. At the population scale, we aim to explain the origins of highly frequent hereditary cancers. We thus hypothesize that pro-oncogenic alleles may neutrally evolve in certain contexts: anti-cancer defenses that are selected in carcinogenic environments may actually compensate cancer progression, and thus allow pro-oncogenic alleles to persist at mutation-drift equilibrium. We finally explore the reciprocal interactions between organism evolution and cancer evolution: especially, we use a nested approach to predict the evolution of resistance and tolerance to cancer, and then we suggest that cancer cells may evolve host manipulation strategies. We notably find that intra-individual evolution favors tolerance over resistance, whereas inter-individual evolution rather favors resistance

Une approche multi-échelle des processus écologiques et évolutifs impliqués dans le cancer

Cancer is a pathology characterized by organism cell transformation and uncontrolled cell proliferation at the expense of the organism. It can affect any tissue in the organism, and can eventually threaten patient survival. This phenomenon is commonly viewed as the result of organism decay during ageing, yet this paradigm fails to embrace the whole complexity of this disease. Cancer progression indeed relies on mutations which fuel differential cell proliferation, and thus it can be described by ecological and evolutionary dynamics. Besides, cancer manifestations are widespread across living organisms, and may be due to the emergence of multicellularity a billion years ago. Cancer has thus always constrained the evolution of organisms. How intra- and inter-organism eco-evolutionary dynamics influence each other across evolutionary times must be investigated to fully understand cancer. Through conceptualization and theoretical approaches, we show that a multi-scale approach offers novel prospects on ecological and evolutionary processes involved in cancer. At intratumor scale, we focus on interactions between cancer cells and on how these interactions structure tumor ecosystems. We notably find that frequent interactions yields lower clonal diversity during tumor expansion. At the population scale, we aim to explain the origins of highly frequent hereditary cancers. We thus hypothesize that pro-oncogenic alleles may neutrally evolve in certain contexts: anti-cancer defenses that are selected in carcinogenic environments may actually compensate cancer progression, and thus allow pro-oncogenic alleles to persist at mutation-drift equilibrium. We finally explore the reciprocal interactions between organism evolution and cancer evolution: especially, we use a nested approach to predict the evolution of resistance and tolerance to cancer, and then we suggest that cancer cells may evolve host manipulation strategies. We notably find that intra-individual evolution favors tolerance over resistance, whereas inter-individual evolution rather favors resistance.Le cancer est une pathologie caractérisée par la transformation de cellules de l'organisme, et leur prolifération incontrôlée aux dépens de l'organisme. Elle peut toucher tout tissu de l'organisme, et menacer la survie des patients à terme. Ce phénomène est souvent interprété comme une dégénérescence de l'organisme au cours du vieillissement, mais ce paradigme ne suffit pas à embrasser toute la complexité de cette maladie. En effet, la progression cancéreuse est basée sur des mutations qui nourrissent une prolifération différentielle des cellules, et elle peut donc être décrite par une dynamique écologique et évolutive. En outre, les manifestations du cancer sont extrêmement répandues dans tout le vivant, et peuvent être attribuées à l'émergence des organismes multicellulaires il y a un milliard d'années. Le cancer a donc toujours représenté une contrainte sur l'évolution des organismes. La compréhension globale du cancer nécessite donc d'élucider comment les dynamiques éco-évolutives intra- et inter-organisme s'influencent mutuellement au cours des temps évolutifs. A l'aide de conceptualisation et d'approches théoriques, nous montrons qu'une approche multi-échelle offre de nouvelles perspectives sur les processus écologiques et évolutifs impliqués dans le cancer. A l'échelle intra-tumorale, nous nous concentrons sur les interactions entre cellules cancéreuses et au rôle structurant que ces interactions peuvent avoir dans les écosystèmes tumoraux. Nous montrons notamment que la fréquence des interactions diminue la diversité clonale durant l'expansion tumorale. A l'échelle populationnelle, nous formulons et explorons une hypothèse sur l'origine de la forte fréquence des cancers héréditaires : les défenses anti-cancer sélectionnées dans les environnements cancérogènes pourraient compenser la progression cancéreuse, et donc autoriser la persistance d'allèles pro-oncogéniques à l'équilibre mutation-dérive. Nous considérons enfin les interactions réciproques entre évolution des organismes et évolution des cellules cancéreuses : spécifiquement l'évolution emboîtée de la résistance et de la tolérance au cancer, et l'évolution de stratégies de manipulation de l'hôte chez les cellules cancéreuses. Nous montrons notamment que l'évolution intra-individuelle favorise la tolérance, tandis que l'évolution inter-individuelle favorise la résistance

Non-cell-autonomous effects yield lower clonal diversity in expanding tumors

Abstract Recent cancer research has investigated the possibility that non-cell-autonomous (NCA) driving tumor growth can support clonal diversity (CD). Indeed, mutations can affect the phenotypes not only of their carriers (“cell-autonomous”, CA effects), but also sometimes of other cells (NCA effects). However, models that have investigated this phenomenon have only considered a restricted number of clones. Here, we designed an individual-based model of tumor evolution, where clones grow and mutate to yield new clones, among which a given frequency have NCA effects on other clones’ growth. Unlike previously observed for smaller assemblages, most of our simulations yield lower CD with high frequency of mutations with NCA effects. Owing to NCA effects increasing competition in the tumor, clones being already dominant are more likely to stay dominant, and emergent clones not to thrive. These results may help personalized medicine to predict intratumor heterogeneity across different cancer types for which frequency of NCA effects could be quantified

PlasForest: a homology-based random forest classifier for plasmid detection in genomic datasets

Plasmids are mobile genetic elements that often carry accessory genes, and are vectors for horizontal transfer between bacterial genomes. The detection of plasmids in large sets of genomes is crucial to analyze their spread and quantify their role in bacteria adaptation and particularly in antibiotic resistance genes propagation. Several bioinformatics methods have been developed to detect plasmids. However, they suffer from low sensitivity ( i.e ., most plasmids remain undetected) or low precision ( i.e ., these methods identify chromosomes as plasmids), and are overall not adapted to identify plasmids in whole genomes that are not fully assembled (contigs and scaffolds). Here, we present PlasForest, a homology-based random forest classifier identifying bacterial plasmid sequences in unassembled genomes. This tool is based on the determination of homologies against a database of plasmid sequences, which allow a random forest classifier to discriminate plasmid contigs. Without knowing the taxonomical origin of the samples, PlasForest identifies contigs as plasmids or chromosomes with an accuracy of 98%. Notably, it can detect 96% of plasmid contigs over 50kb with 3.3% of false positives. PlasForest outperforms other currently available tools on test datasets by being both sensitive and precise. We implemented this tool in a user-friendly pipeline that can identify plasmids in large datasets in a reasonable amount of time

Metastasis and the evolution of dispersal

International audienceDespite significant progress in oncology, metastasis remains the leading cause of mortality of cancer patients. Understanding the foundations of this phenomenon could help contain or even prevent it. As suggested by many ecologists and cancer biologists, metastasis could be considered through the lens of biological dispersal: the movement of cancer cells from their birth site (the primary tumour) to other habitats where they resume proliferation (metastatic sites). However, whether this model can consistently be applied to the emergence and dynamics of metastasis remains unclear. Here, we provide a broad review of various aspects of the evolution of dispersal in ecosystems. We investigate whether similar ecological and evolutionary principles can be applied to metastasis, and how these processes may shape the spatio-temporal dynamics of disseminating cancer cells. We further discuss complementary hypotheses and propose experimental approaches to test the relevance of the evolutionary ecology of dispersal in studying metastasis

Cancer Is Not (Only) a Senescence Problem

International audienceAge is one of the strongest predictors of cancer and risk of death from cancer. Cancer is therefore generally viewed as a senescence-related malady. However, cancer also exists at subclinical levels in humans and other animals, but its earlier effects on the body are poorly known by comparison. We argue here that cancer is a significant but ignored burden on the body and is likely to be a strong selective force from early during the lifetime of an organism. It is time to adopt this novel view of malignant pathologies to improve our understanding of the ways in which oncogenic phenomena influence the ecology and evolution of animals long before their negative impacts become evident and fatal

The importance of cancer cells for animal evolutionary ecology

Reciprocal interactions between hosts, their symbionts and their oncobiota (cancer cell communities) are yet to be studied in detail. Considering malignant cells in addition to the holobiont perspective allows greater understanding of the processes governing both host phenotypes and cancer dynamics