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Cancer and Evolution: An international workshop in Arcachon, France

6 October - 7 October

This workshop will explore cancer from an evolutionary perspective, with a strong focus on how cancer appeared and evolved and on the different forms of cancer across taxa.

Schedule

Speakers

This workshop will gather the best world-leading experts on this issue:

  • David Bilder (University of Berkeley, USA), “Ancient origins of tumor-host interactions: insights from the Drosophila model”
  • Thomas Bosch (Christian-Albrechts-Universität zu Kiel, Germany), “Hydra´s stable microbiome: key for escaping cancer?”
  • James DeGregori (Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, USA), “Somatic evolution – causes and consequences”
  • Mathieu Giraudeau (CNRS, La Rochelle, France), “Wildlife species as a source of inspiration in our fight against cancer?”
  • Vera Gorbunova (Rochester, USA), “Evolution of tumor suppressor and longevity mechanisms: from bats to whales”
  • Crisanto Gutierez (Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain), “The Retinoblastoma/E2F pathway, an evolutionary ancient module in plants and animals”
  • Hanna Kokko (Zürich, Switzerland), “Peto’s paradox in lemurs: insights from fitting the multi-step model of cancer to lifespan data”
  • Carlo Maley (Arizona State University, USA), “The promise of evolution for the biggest problems in cancer”
  • Elizabeth Murchison (Cambridge University, United Kingdom), “Transmissible cancers in mammals”
  • Samir Okasha (Department of Philosophy, University of Bristol, United Kingdom), “Should cancer be viewed through the lens of social evolution theory?”
  • Joshua D. Schiffman (MD, Division of Pediatric Hematology/Oncology, Department of Pediatrics and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA; Peel (“Elephant”) Therapeutics, Inc., Salt Lake City, Utah, USA and Haifa, Israel), “Elephants, Evolution, and Cancer: How elephants contributed to a new biotech focused on evolutionary medicine”

 

Flash talks

  • – Bertrand Daignan-Fornier (IBGC, CNRS, Bordeaux, France), Cancer and multicellularity: general ideas and an experimental approach
  • – Lucie Laplane (IHPST & Gustave Roussy, Paris, France), Unraveling assumptions in clonal evolution
  • – Maël Lemoine (ImmunoConcept, University of Bordeaux, France) & Thomas Pradeu (ImmunoConcept, CNRS, France), Do anticancer mechanisms exist?
  • – Benjamin Spada (ImmunoConcept, CNRS, France)

 

Organizers

– Bertrand Daignan-Fornier (IBGC, CNRS, Bordeaux, France)

– Mathieu Giraudeau (LIENSs, CNRS, La Rochelle, France)

– Thomas Pradeu (ImmunoConcept, CNRS, France)

– Benjamin Spada (ImmunoConcept, CNRS, France)

 

 

Abstracts

 

David Bilder (Berkeley, USA), Ancient origins of tumor-host interactions: insights from the Drosophila model

There is a large gap between the deep understanding of mechanisms driving tumour growth and the reasons why patients ultimately die of cancer. It is now appreciated that interactions between the tumour and surrounding non-tumour (sometimes referred to as host) cells play critical roles in mortality as well as tumour progression, but much remains unknown about the underlying molecular mechanisms, especially those that act beyond the tumour microenvironment. Drosophila has a track record of high-impact discoveries about cell-autonomous growth regulation, and is well suited to now probe mysteries of tumour – host interactions. Here, we review current knowledge about how fly tumours interact with microenvironmental stroma, circulating innate immune cells and distant organs to influence disease progression. We also discuss reciprocal regulation between tumours and host physiology, with a particular focus on paraneoplasias. The fly’s simplicity along with the ability to study lethality directly provide an opportunity to shed new light on how cancer actually kills.

 

Thomas Bosch (Christian-Albrechts-Universität zu Kiel, Germany), “Hydra´s stable microbiome: key for escaping cancer?”

All animals are multiorganismal associations of a host and its specific microbes interacting with a given environment. An intricate balance between cell dynamics within the host, associated microbiota, and their proper adjustment to the environment maintain the integrity of such a metaorganism. The extent to which disturbances in the resident microbiota can compromise an animal’s health is poorly understood. Hydra is one of the evolutionary oldest animals with naturally occurring tumors. We have shown earlier that dysbiosis or absence of microbes results in immunologic and neurologic deficits. Here we aim at the cancer-microbiome connection and show a causal relationship between microbial dysbiosis and tumorigenesis in Hydra. The observation in an organism that shares deep evolutionary connections with all animals points to the crucial role of commensal bacteria in maintaining tissue homeostasis and adds support to thinking in the direction of “ecological oncology”. We conclude that microbial community interactions are essential for the host health and that understanding of the interactions of the host with the microbiome will change the way we see and treat cancer.

 

Marco De Dominici, Edward J Evans, Fabio Marongiu, Kelly C. Higa, Andrew Goodspeed, Andrii I Rozhok, Clara Troccoli, Eric M. Pietras and James DeGregori, “Somatic evolution – causes and consequences”

Why do we get cancer? Why is cancer highly associated with old age, and why are insults like smoking associated with increased risk of cancers? Of course, these contexts all cause mutations, and some of these mutations can contribute to malignant phenotypes. But we now understand that carcinogenesis is much more complex than originally appreciated. There are microenvironmental forces that both impede and promote cancer evolution. Just as organismal evolution is known to be driven by environmental changes, somatic evolution in our bodies is similarly driven by changes in tissue environments, whether caused by the normal process of aging, by lifestyle choices, or by extrinsic exposures. Environmental change promotes selection for new phenotypes that are adaptive to the new context. In our tissues, aging or insult-driven alterations in tissues drives selection for adaptive mutations, and some of these mutations can confer malignant phenotypes. We will discuss how natural selection has invested in animal tissue landscapes so as to limit the fitness-reducing effects of malignancies through reproductive years, and how youthful tissues are tumor suppressive through all stages of cancer progression (and how this protection wanes in older ages where animal contributions to reproduction are minimal).

We have been using mouse models of cancer initiation, mathematical models of cellular evolution, and analyses of human tissue samples to better understand the evolutionary forces that control somatic cell evolution and thus cancer risk. By reanalyzing data from many groups, we have quantified the numbers of cells in our tissues that possess cancer-associated mutations, and how these change as we age. We have also leveraged a highly sensitive mutation-detection method (duplex-seq) to analyze mutational landscapes in the lungs of people of different smoking statuses, showing how smoking promotes strong selection for oncogenic mutations. Finally, using mouse models and focusing on cancer initiation within the hematopoietic system and the lung, we have shown that aging and inflammation dependent changes in tissue environments dramatically dictate whether cancer-causing mutations are advantageous to stem cells in our tissues, with potential to impact tissue function and malignancy.

Mathieu Giraudeau (CNRS, La Rochelle), “Wildlife species as a source of inspiration in our fight against cancer”

Although the aetiology of cancer in humans and laboratory model organisms has received ample attention, many aspects of cancer remain poorly understood or seriously understudied. For instance, it is now widely recognized that cancer not only affects humans, but it occurs in most species of the animal kingdom, from hydra to whales. Despite increasing interests, our knowledge on cancer in wildlife is extremely limited, even regarding its prevalence in major vertebrate clades, its causes, consequences, life-history, genetic or physiological predictors or how environmental changes contribute to emerging cancer cases. Accurate estimates on cancer in wildlife promise extremely valuable information on oncogenic processes, as the limited research conducted on non-standard model organisms already provided tremendous insights on the natural mechanisms of cancer resistance. Very low cancer rates are ensured by duplications of the TP53 tumor-suppressor gene in elephants, overproduction of high molecular mass hyaluronan in the naked mole rats, interferonmediated concerted cell death in the blind mole rat and reduced growth hormone (GH)–insulin-like growth factor-1 (IGF1) signaling and microRNA (miRNA) changes in bats. Despite its value, robust cancer prevalence data on animals are surprisingly limited. Our research, at the interface of oncology, physiology, genetic, cellular and evolutionary biology, aims to unravel the cross-species diversity of cancer resistance, and highlight future avenues in the identification of efficient tumour-suppressor mechanisms. Moreover, our results are expected to provide key information about cancer in wildlife, which is a top-priority due to the accelerated anthropogenic change of the past decades that might favor cancer progression in wild populations.

 

Vera Gorbunova (Rochester, USA), “Evolution of tumor suppressor and longevity mechanisms: from bats to whales”

Nature has created mammalian species with dramatic diversity of aging rates. We explore this diversity to understand the mechanisms of aging and identify targets for antiaging interventions. I will present new data related to anticancer mechanisms in bats and whales. I will also talk about epigenetic features of long-lived species and how SIRT6 can be targeted to achieve epigenetic rejuvenation.

 

Crisanto Gutierrez, “The Retinoblastoma/E2F pathway, an evolutionary ancient module in plants and animals”

The identification of the Retinoblastoma (Rb) tumor suppressor in human cells paved the way for studies showing the relevance of Rb and its associated E2F/DP transcription factors in the control of cell cycle progression. It also led to the assumption that the Rb/E2F module could be an evolutionary acquisition of mammalian cells. However, a discovery a few years later challenged that view after the identification of homologues of human Rb in the maize genome (1,2), and subsequently in other plant species, including unicellular algae. This was particularly striking, since plants were considered to have a cell cycle regulation similar to that of S. cerevisiae that lacks Rb. The isolation of plant RBR was preceded by the finding that the LxCxE motif of the plant geminivirus RepA was required for efficient viral DNA replication (3). These studies were further expanded with the identification of Arabidopsis D-type cyclins, which contains an LxCxE Rb-interaction motif, and E2F and DP family members (4). The Arabidopsis RBR gene is essential, and lack of function mutants show multiple defects including hyperplasia of several organs (5). Arabidopsis RBR also plays a key role in controlling cell cycle progression rate during plant development (6), all aspects that will be discussed in the context of cancer development.

References:

1. Xie et al. EMBO J. 15, 4900-4908 (1996)

2. Grafi et al. Proc Natl Acad Sci U S A 93, 8962-8967 (1996)

3. Xie et al. EMBO J. 14, 4073-4082 (1995)

4. Desvoyes et al. J Exp Bot. 65, 2657-2666 (2014)

5. Desvoyes et al. Plant Physiol. 140. 67-80 (2006)

6. Desvoyes and Gutierrez. EMBO J. 39, e105802 (2020).

 

Hanna Kokko, Peto’s paradox in lemurs: insights from fitting the multi-step model of cancer to lifespan data

Peto’s paradox refers to the curious fact that a priori one might expect large-bodied organisms to have the highest cancer incidence, but graphs of this relationship are typically flat. By now, there are several exciting findings how specific large species have evolved cancer suppression mechanisms. We take a different approach, aiming to find statistical evidence of different cancer defences in data of known aged animals that have, or have not, developed cancer at the age of death. We use AIC modelling to fit parameters of the multi-step model to cancer data in lemurs, and show that there is evidence for defences becoming stronger in larger organisms, at a sufficient level to produce the flat line indicative of Peto’s paradox. The data show evidence that the expected cancer-free lifespan is typically larger than the realized lifespan. While this does not indicate that species are fully cancer-proof (due to stochasticity of oncogenesis, some cancers arise earlier than the statistical mean time to their arrival), it does mean that natural selection is able to push cancer to old enough ages to make it a relatively uncommon cause of death  compared to other sources of mortality, and that its ability to do so is roughly constant across all body sizes. We will also comment on differences between males and females in this respect.

 

Carlo Maley, The promise of evolution for the biggest problems in cancer

Because cancer is an evolutionary disease at the cell level, evolutionary biology can inform and help to solve many of the biggest problems we face in cancer research and treatment. I will show how evolution can help address the problems of cancer initiation, risk stratification, cancer prevention, early detection of cancer, why cancers metastasize and how we might prevent that, improving cancer therapy and preventing therapeutic resistance, and most importantly, preventing deaths due to cancer. I will illustrate these points with recent results from my lab in some cases, and from collaborators in others. There is great promise in bringing the ideas and tools of evolutionary biology (and ecology) to bear on cancer.

 

Elizabeth Murchison, “Transmissible cancers in mammals”

Cancer arises when mutations drive cells of the body to abandon their usual functions and to instead embark upon a “selfish” evolutionary programme underpinned by abnormal growth. Most cancers exist only within the bodies of the hosts that spawn them; rarely, however, cancers can acquire adaptations allowing them to spread between individuals. In such transmissible cancers the cancer cells themselves become agents of infection. Elizabeth Murchison will discuss recent research on the origins and evolution of the naturally occurring mammalian transmissible cancers affecting dogs and Tasmanian devils.

 

Samir Okasha, Should cancer be viewed through the lens of social evolution theory? 

Cancer is often conceptualized in terms of selective conflict between cell and organism: cancer cells pursue a strategy of short-term proliferation to the detriment of the collective (Greaves 2015, Aktipis 2020). On this view, cancer involves a form of multi-level selection in which the cancerous cell phenotype is favoured by selection at the cell level but opposed by selection at the organism level. This explains the widespread tendency to apply descriptors from social evolution theory to cancer. Thus malignant cells in a neoplasm are described as “selfish cheats” seeking to benefit themselves at the expense of the collective, by contrast with the “cooperative” behavior of normal somatic cells. The tendency to view cancer in this way is manifest not just in the language biologists use but also in the explanations they give. For example, it is often argued that the abnormal behaviour of cancer cells, though puzzling at first sight, becomes explicable once we realize that they differ genetically from normal somatic cells, thanks to mutations and / or chromosomal re-arrangements. This argument invokes one of the central principles of social evolution theory, namely that clonally related units have identical interests so will be selected to cooperate, while genetically different units will not.

Recently, Gardner (2015) and Shpak and Lu (2016) have argued that cancer is not a true case of multilevel selection, that cancer cells should be not regarded as cheats, and that the analogy between anti-cancer adaptations and suppression mechanisms in social groups is misleading. Their basic argument is that cancer is an evolutionary dead-end, since a cancerous cell lineage dies when its host organism dies (apart from in extremely rare cases of transmissible tumours). Thus cancer is fundamentally dissimilar from paradigm cases of multilevel selection, they argue. This “evolutionary dead-end” argument is powerful but not decisive. By drawing on the (hypothesised) link between cancer and the evolution of multicellularity, the notion that cancer represents a form of selective conflict between cell and organism can be partially salvaged; and thus the propriety of viewing cancer though a social evolution lens can be defended. I illustrate this with reference to Buss’s (1987) work on the origins of multicellularity, and the more recent “atavistic hypothesis” of Davies and Lineweaver (2011).

 

Joshua D. Schiffman, “Elephants, Evolution, and Cancer: How elephants contributed to a new biotech focused on evolutionary medicine”

Elephants are naturally cancer resistant, potentially due to changes in the genetic sequence of elephant TP53 (EP53) and the amplification of at least 20 TP53 retrogenes. Defining the mechanisms of action responsible for cancer suppression in elephants by EP53 and its retrogenes is being investigated for evolutionary insight that can be translated into effective therapeutics to treat human cancer. We have shown that EP53-RETROGENE 9 (EP53-R9) encodes a truncated p53 protein that can induce apoptosis of human cancer cells through a transcription-independent mechanism. The EP53-R9 protein is translocated to the mitochondria where it interacts with pro-apoptotic genes, leading to caspase activation and cancer cell death. To further characterize elephant TP53 mechanisms of cancer suppression, we generated transgenic mice. These mice have full length EP53 replacing mouse TRP53, along with EP53-R9 containing an inducible promoter. Experiments are currently underway to determine if the mice expressing EP53 with or without EP53-R9 develop less cancer than mice with TRP53. EP53 expression is a strong inducer of human cancer cell apoptosis compared to human TP53, especially when combined with EP53-R9. Delivery of EP53 genes into human cancer cells overcomes chemoresistance and led to the creation of Peel Therapeutics, a biotech company focused on unlocking evolutionary biology to treat patients with cancer and inflammation (“Peel” is Hebrew word for elephant). Peel Therapeutics has been developing EP53-loaded nanoparticles that reach tumors in vivo, express as proteins, and activate p53 target genes. EP53 nanoparticles are now in early stages of investigation for their future potential as therapy for p53 deficient tumors, including Li-Fraumeni Syndrome (LFS)-associated cancers. Peel Therapeutics has several other evolution-based drugs in development, including an ongoing early phase clinical trial for PEEL-224 that originates from a DNA topoisomerase 1 inhibitor found in a tree toxin (Camptotheca acuminata). The third drug being developed by Peel Therapeutics evolved in newborns to prevent neutrophil extracellular trap (NET) formation and subsequent inflammation with immunothrombosis. This natural neutrophil targeting peptide (NTP) may have a future therapeutic role in blocking cancer-associated thrombosis, preventing metastasis, and enhancing immunotherapy for patients with cancer. Together with academic partners, including the Arizona Cancer and Evolution (ACE) Center, other species are being explored for their natural cancer resistance and their potential to contribute to novel cancer therapies. The study of evolution and cancer is a growing field that can lead to important discoveries to help humans, and other animals, with cancer.

 

Venue

Hôtel de la Plage, Arcachon, France

10, Avenue Nelly Deganne
33120 Arcachon, Tel. +33 (0)5 56 83 06 23; email:

Details

Start:
6 October
End:
7 October
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Venue

Arcachon, Hotel de la Plage
10, Avenue Nelly Deganne
Arcachon, 33120 France

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