Tag: workshop

Cancer and Evolution: An international workshop in Arcachon, France

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: infos@hotelarcachon.com

Workshop, Interdisciplinarity in Neuroscience: What are the issues?

The study of the brain, because of the immense complexity of this organ, has involved scientific research strategies at very different scales and levels of organization. As a result, neuroscience can be considered as an interdisciplinary nebula rather than as a discipline with well-defined boundaries. The evolution of instruments for measuring, studying, or experimenting on the brain, but also the diverse purposes of neuroscience research (clinical or therapeutic, explanatory or descriptive, theoretical) have also implied collaborations between disciplines that are sometimes very distant. The goal, often stated but rarely achieved, of an integrative approach to these different levels, scales, and purposes presupposes theoretical and institutional conditions for interdisciplinary dialogue that are difficult to implement due to various factors (specialization of scientist’s training, pressure to publish in an identified field, intrinsic epistemic difficulties of interdisciplinary or even inter- level collaborations).
The purpose of this workshop is to initiate a reflection within the Bordeaux Neurocampus on the conditions under which these collaborations and this dialogue between experimental or theoretical approaches at different scales of the brain, with different purposes and different study instruments can be more fruitful. In the background of this reflection, we hope to be able to propose a program of intervention of philosophy in the field as one of the actors of the study of the brain likely to contribute to the interdisciplinary development of new theoretical frameworks and innovative hypotheses to embrace the complexity of the brain in an original way.

Venue

CNRS UMR 5536 RMSB, meeting room, University of Bordeaux, Carreire Campus
146 rue Léo Saignat 33076 Bordeaux
 

Program

 
July 7, 2022
9:30-10 AM: Cédric Brun and Jan Pieter Konsman: Welcome and presentation of workshop
10-11 AM: Plenary talk 1
Isabella Sarto-Jackson: Complexity-driven interdisciplinarity: promises and pitfalls (30 min presentation + 20 -30 min Q&A)
11-11:10 AM: Break
Thematic session 1: Integratibility of neuroscience research and interdisciplinarity
11:10-11:40 AM:
Léa Peltier: Computation in Neuroscience and Philosophy. From interdisciplinarity to intercultural dialogue, an anthropological perspective (15-20 min + 10-15 min Q+A)
11:40-12 AM: Round table 1: integratibility of neuroscience research and interdisciplinarity
2-3 PM: Plenary talk 2
Markus Kunze: Neuroscience and the interpretation of human behavior: searching for a framework for interdisciplinary exchange (30 min presentation + 20-30min Q&A)
3-3:10 PM Break
Thematic session 2: Diversity of models and interdisciplinarity
3:10-3:40 PM:
Jérôme Badaut: Overcoming the barriers in translational neuroscience by diversity in models? (15-20 min presentation + 10-15 min Q+A)
3:40 PM-4:10 PM:
Muriel Darnaudery: Early life adversity and (mental) health: my short journey into interdisciplinarity (15-20 min presentation + 10-15 min Q+A)
4:10-4:40 PM:
Fréderic Villéga: Pitfalls and challenges of a clinician/researcher collaboration: a story around observations and experiments (15-20 min presentation + 10-15 min Q+A)
4:40-5 PM: Round table 2: Diversity of theoretical models and interdisciplinarity

July 8, 2022

 
9:30-10:30 AM: Plenary talk 3
Fridolin Gross: The explanatory role of machine learning in molecular biology
10:30-10:40 AM: Break
Thematic session 3: Computational modelling, theoretical neuroscience and interdisciplinarity
10:40-11:10 AM:
Thomas Boraud: Complexity and Haphazard dimensionality reduction (15-20 min presentation + 10-15 min Q+A)
11-10-11:30 AM: Round table 3: Computational modelling, theoretical neuroscience and interdisciplinarity
11:30-11:45: Conclusion

 
Organized by Jan Pieter Konsman & Cédric Brun
Workshop funded by the PhilInBioMed Network and the Region Nouvelle Aquitaine

Workshop with Deborah Gordon (Stanford University) – Interaction networks: From ant colonies to the immune system

Presentation of the topic

In her work on ants, Deborah Gordon has shown that collective behavior operates without central control, through interactions among individuals. Like any phenotypic trait, the process that regulates collective behavior evolves in relation with a dynamic environment. Similar ecological constraints, in many natural systems from cells to ants, may correspond to similar algorithms that regulate collective outcomes. Some important aspects of the dynamics of the environment include stability, the threat of rupture or disturbance, the ratio of inflow and outflow of resources or energy, and the distribution of resources. These correspond to the dynamics of collective behavior, including the rate of amplification, how feedback instigates and inhibits activity, and whether information is spatially centralized. The collective behavior of ant colonies is based on simple olfactory interactions. Ant species differ enormously in the algorithms that regulate collective behavior, reflecting diversity in ecology.  An example is the contrast between the regulation of foraging by harvester ants in the desert, where life is tough but stable, and by arboreal turtle ants in the tropical forest, where life is easy but unpredictable.

The general aim of this workshop is to explore the shared features between ant colonies and the functioning of the immune system. Are they similar networks? Do encounters between immune cells look like ant encounters? Can one find algorithms, or general rules, that would help predict the behavior of both ants and immune cells? This workshop gathers around Deborah Gordon a diversity of researchers: philosophers of science, specialists of systems biology, immunologists and neuroscientists. Collectively, they will assess to what extent the analogy between ant networks and immune networks is fruiful.

 

Deborah M. Gordon is a Professor in the Department of Biology at Stanford University.

She received her PhD from Duke University, then did postdoctoral research in the Harvard Society of Fellows, at Oxford University, and the Centre for Population Biology at Silwood Park, University of London, and joined the faculty at Stanford in 1991.

Prof. Gordon’s lab group studies the collective regulation of behavior and collective identity, and how collective behavior functions ecologically. She discovered that ants use the rate of simple olfactory contacts to decide what task to perform, and that feedback based on such contacts regulates colony activity such as foraging. A unique long-term study tracking a population of harvester ant colonies in the desert of the southwestern US shows how evolution is currently shaping collective behavior in a natural population.

She is the author of two books, Ants at Work (Norton 2000) and Ant Encounters: Interaction Networks and Colony Behavior (Primers in Complex Systems, Princeton University Press, 2010), and awards include a Guggenheim Fellowship and fellowships at the Center for Advanced Study in Behavioral Sciences.  Links to articles and talks for the general public are on the home page, and links to scholarly articles are on the publications page of http://www.stanford.edu/~dmgordon/.

 

Participants:

Serge Ahmed (IMN – UMR 5293 – CNRS / Université de Bordeaux)
Wiebke Bretting (Immunoconcept – UMR 5164 – CNRS / Université de Bordeaux)

Anne Coubray (Immunoconcept – UMR 5164 – CNRS / Université de Bordeaux)
Gregor Greslehner (Immunoconcept – UMR 5164 – CNRS / Université de Bordeaux)
Fridolin Gross (Universität Kassel, Germany / IFOM (Istituto FIRC di Oncologia Molecolare), Milan, Italy)
Jan-Pieter Konsman (INCIA – UMR 5287- CNRS / Université de Bordeaux)

Maël Lemoine (Immunoconcept – UMR 5164 – CNRS / Université de Bordeaux)
Jean-François Moreau (Immunoconcept – UMR 5164 – CNRS / Université de Bordeaux)
Thomas Pradeu (Immunoconcept – UMR 5164 – CNRS / Université de Bordeaux)
Elena Rondeau (Immunoconcept – UMR 5164 – CNRS / Université de Bordeaux)

 

This workshop is organized thanks to the support of the ERC IDEM project (Grant #637647).

 

Workshop with Ezio Laconi (Cagliari) – Cancer and the Tumor Microenvironment: Development, Evolution, and the Microbiota

The ERC IDEM is proud to host this one day workshop with Ezio Laconi on Cancer and the Tumor Microenvironment: Development, Evolution, and the Microbiota.
 
Workshop program

 

 
Plenary Speaker
 

Ezio Laconi (Department of Biomedical Sciences and Biotechnology, University of Cagliari, Italy)
 
Development versus evolution in the pathogenesis of cancer
It is rather surprising that the terms “development” and “evolution” are both used, often interchangeably, to describe the unfolding of carcinogenic process. However, there is increasing awareness on the essential difference in the meaning of these two definitions with reference to neoplastic disease. Evidence will be discussed to suggest that the concepts of development and evolution are both pertinent to describe carcinogenesis; however, they appropriately apply to distinct phases of the multistep process. Such distinction bears important implications for disease analysis and management.
 
 

Speakers
 

Elena Rondeau (ImmunoConcept, CNRS, University of Bordeaux)
Understanding cancer progression and its control: An analysis of immune contribution to metastasis causality
Ongoing progress in cancer research is improving our comprehension of the spatial and temporal complexity of tumour progression, indeed characterised by the pleiotropic involvement of the tissue environment at different stages of the illness (Plutynski 2018). While supplementing our thorough appreciation of the cell-intrinsic properties of transformation, these advances still face serious difficulties, such as those linked to tumour recurrence and systemic spread.
Metastasis is currently the leading cause of cancer mortality, correlating with disease severity and resistance to conventional therapy. Beyond its accepted description as a multistep process resulting in the development of secondary tumours at distant sites, certain observations remain partly unexplained and conceptually challenging. For instance the report of organ specificity for secondary growth, describing the apparent tropism of primary tumour cells for particular metastatic tissues, complicates the understood causality of cancer cell dissemination and subsequent implantation.
The “seed and soil” theory of metastasis, initially coined by Paget (1889), stipulates that such patterns can be explained by favourable interactions between circulating tumour cells (the “seed”) and specific microenvironments encountered during their migration (the “soil”). While maintaining an illustrative role, its exact premises and implications may benefit from a revisited analysis in the light of recent clinical and experimental observations. In particular, the evidence of distant “pre-metastatic niche” preparation, involving both tumour-derived factors and pre-existing host components hijacked by the malignant context, could defy the explicative power of the analogy.
Triggered by these considerations is the objective to decipher the implication of the immune system in cancer progression, given the delicate balance between its protective and pro-tumoral activities. Indeed pre-metastatic processes are frequently associated with immune cell recruitment, inflammatory signalling and structural remodelling, with a direct contribution of these features to tumour development and secondary seeding. As a matter of fact, those populations of suppressive and pro-invasive immune cells may actively encourage “seed” persistence and enable distant metastasis by establishing a hospitable and/or attractive environment in future “soils”.
Hence the pressing question of determining the exact role of host immunity in metastasis causality: to what extent, and how, do the immune actors of cancer progression contribute to the preparation and specificity of secondary sites? Underlying the conceptual framework of the “seed and soil” hypothesis, would this reflection help better understand the relative contributions of pro-metastatic factors, and how may it affect practical and therapeutic considerations?
In my research, I propose to address this issue from both a conceptual and an experimental point of view, through a case study of metastatic tropism in a mouse model of breast cancer known to specifically disseminate to the lungs. The characteristics of a subset of pro-tumoral myeloid cells are monitored through the course of tumour evolution and in differential environments, in an attempt to better understand their early accumulation at pre-metastatic sites.
 
 

Jean-François Moreau (ImmunoConcept, University of Bordeaux)
Is there a place for autoimmunity in immunotherapies ?
The immunotherapies seems to  be the magic bullet to cure patients with some types of cancer. While the mutation load is coming to mind and is sustained by many studies to explain the increased immune response toward the tumor, it should not be overlooked that ipilimumab (targeting CD152/CTLA-4) or nivolumab (targeting PD-1) or atezolizumab (targeting PD-L1) among others, do alter the fine tuning of the level of autoreaction within the immune system which is deeply encryted into the functionning of the adaptive immune system. Usually considered as the underpinnings of the tolerance mechanisms, we will explain the basis of it and its potential consequences in the natural evolution of cancer and in the response to the today immunotherapies in the field of cancer.
 
 
 

Christine Varon (BaRITOn, University of Bordeaux)
 
Helicobacter infection, cancer stem cells and gastric cancer
Gastric cancer is the third leading cause of cancer mortality in the world. Chronic infection with Helicobacter pylori, a class 1 carcinogen, is the main infectious cause of cancer in the world, being responsible for more than 90% of the non-cardia gastric carcinomas (GC). The recent discovery of the existence of cancer stem cells (CSC) at the origin of the GC has opened new perspective for the development of new therapy targeting gastric CSCs. Our group is focused on the study of the cellular and molecular mechanisms leading to the emergence of CSC in GC induced by chronic infection with H. pylori. We have developed mouse xenograft models of patient’s derived primary GC, allowing to reproduce in mice tumours like those of the patients. Using these models as well as in vitro tumorspheres assays, we have characterized some cell surface markers of enrichment of CSC, among them CD44 and ALDH. In a mouse model of H. pylori-induced gastric carcinogenesis, we have shown that gastric CSCs may originate from both local or bone-marrow derived (BM) stem cells. In this context, chronic infection with H. pylori induced an epithelial to mesenchymal transition (EMT) leading to the emergence of CD44+ cells possessing mesenchymal and stem cell properties. These cells participated to metaplastic and dysplastic lesions to give rise, after additional epigenetic and mutational events, to the emergence of CSCs and adenocarcinoma. Based on these complementary in vitro and in vivo models, our current research aims to characterize the signaling pathways involved during H. pylori-induced EMT and CD44+ cells, and driving the CSC self-renewal and tumorigenic properties, in order to further specifically target them and inhibit CSC properties and GC progression.
 
 

Thomas Pradeu (ImmunoConcept, CNRS, University of Bordeaux)
“How can the microbiota influence tumor progression and cancer treatment?”
It is increasingly recognized that almost all organisms are hosts to myriads of microbes, which often play functional roles in the host. Recent research has revealed that the microbiota could have a strong impact on cancer development (Zitvogel et al., 2018). The microbiota plays a role in carcinogenesis, both locally and at distant sites. Furthermore, the microbiota can influence how the host responds to anti-cancer therapies. Several of these therapies, including chemotherapy and several immunotherapies, show reduced efficacy in germ-free mice as well as in mice treated with broad-spectrum antibiotics, or in mice lacking specific bacteria that stimulate the immune system (Iida et al., 2013; Sivan et al., 2015; Vétizou et al., 2015; Viaud et al., 2013). In parallel, it was observed in patients that certain bacteria had a positive impact on host responses to some immunotherapies. Initial correlational observations were then confirmed causally, by FMT from patients to mice, which suggested that “responding” and “non-responding” phenotypes could be transferred from humans to mice, with some particular bacteria playing a crucial role in this process (Gopalakrishnan et al., 2018; Matson et al., 2018; Routy et al., 2018).
This research raises many interesting issues, at the interface between biology, medicine, and philosophy:
i) Should the influence of the microbiota on tumor development be considered as one illustration among others of the increasingly acknowledged role of the tumor microenvironment (TME)?
ii) Do such studies demonstrate mere correlation, or causality? (Thomas and Jobin, 2015) What are the mechanisms underlying the influence of the microbiota on tumor development, and what is the role of the immune system in this process?
iii) Is it possible to better characterize the specific bacteria that seem to have a positive role in host’s response to cancer treatment?
iv) More generally, what does the impact of the microbiota on cancer development tell us about our definition of cancer?
 
References
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Workshop on robustness: Philosophical, biological and medical issues (Pey Berland, University of Bordeaux, France)

Fridolin Gross: "Robust mechanisms or mechanisms of robustness?"

Marie-Elise Truchetet & Thomas Pradeu: "Re-thinking our understanding of immunity: Robustness in the tissue reconstruction system"

Jonathan Sholl: "Physiological robustness"

Paul Griffiths: Beyond canalisation: robustness in developmental systems

Elena Rondeau: "Understanding cancer progression and its control: the (im)balance between tissue construction, destruction and reconstruction?"

Jan Pieter Konsman: "Central components of the systemic inflammatory response confer robustness to the infected host through functionally redundant regulatory processes"

Chaired by Maël Lemoine.