Fourth Philosophy of Cancer Biology Workshop University of Bordeaux, Campus Victoire Amphi Sigalas 3ter Place de la Victoire, 33000 Bordeaux, France
Information and registration: Cancer Workshop <https://www.philinbiomed.org/event/fourth-philosophy-of-cancer-biology-workshop/> The main goal of this workshop is to provide a forum where philosophers of biology/medicine, scientists, and medical doctors meet to discuss the biological and medical science of cancer. This workshop will be available through Zoom. Registration is required. This workshop will be recorded and available on our Youtube channel. Plenary speakers Maria Blasco <https://www.cnio.es/en/personas/maria-a-blasco-2/> (Centro Nacional de Investigaciones Oncológicas, Madrid, Spain) Title and abstract TBA *** Andrew J. Ewald <https://cellbio.jhmi.edu/people/andrew-ewald-ph-d/> (Professor and Director of Cell Biology, Johns Hopkins Medical School; Professor of Oncology and Co-Leader of the Cancer Invasion and Metastasis Program, Sidney Kimmel Comprehensive Cancer Center) Unraveling the logic of cancer through analysis of cellular and molecular dynamics >From a patient perspective, the key distinction among tumors is whether the cancer cells remain confined with the tissue barriers of the original organ (localized disease, 99% 5 year survival) or whether they have spread through the body and formed new tumors in distant organs (metastatic disease, 27% 5 year survival). These facts led us to focus on understanding how breast cancer cells acquire the ability to metastasize. Metastasis is difficult to study directly because it occurs deep inside the body, takes place over months to decades, and involves many changes in the cancer cell and its microenvironment. To overcome these barriers, we have developed a series of ‘3D culture’ assays in which we explant tissue from normal organs or breast tumors into 3D gels composed of the structural proteins that surround cells in the body (extracellular matrix; ECM). These assays enable us to study how tumors grow, invade, enter blood vessels, evade the immune system, and establish new metastatic tumors. We use techniques from genetics and bioinformatics to identify the molecular programs driving metastatic cell behaviors and determine ways to stop those behaviors. We use techniques from tissue engineering and immunology to understand how the ‘tumor microenvironment’ conspires with cancer cells to drive metastasis and how we can leverage those insight to identify patients at the greatest risk of metastatic recurrence. I will present select examples from these research programs to provide context for a broader discussion of what we can glean of the underlying logic of cancer progression. Our starting framework is: (1) that developing epithelia exhibit most of the features we might think of as characteristic of cancer progression, including proliferation, ECM-degradation, and cell migration, (2) that these cell behaviors can be induced with simple molecular signals but that key decisions typically involve many molecular exchanges, and (3) that a key barrier that must be overcome during metastatic progression is the cell-death wiring that enforces tissue compartmentalization and multicellularity. I look forward to a robust trans-disciplinary discussion. *** Carlo Maley <https://www.sols.asu.edu/carlo-maley> (Arizona State University, USA) What is cancer? A view across the tree of life Cancer has usually been defined clinically by how it appears in humans, for understandable reasons. It is typically defined as a neoplasm that invades through a basement membrane or metastasizes to a distant tissue. However, cancer is a problem for any multicellular organism, and many of those organisms do not have basement membranes. The fundamental nature of cancer can be better understood by investigating the commonalities across the different branches on the tree of life that have independently evolved multicellularity, and how those foundations of multicellularity break down. I will also touch on our investigations across species to try to understand patterns of cancer susceptibility and resistance in animals. *** Nicholas McGranahan <https://www.ucl.ac.uk/cancer/research/department-oncology/cancer-genome-evolution-research-group> (London, UK) Exploring Cancer Evolution and Immune Escape Cancer development within an individual is an evolutionary process. This has important clinical implications for cancer prevention and therapy, as well as our understanding of cancer progression and metastatic spread. Historically, applications of evolutionary biology to understand and control cancer progression have received relatively little attention. Evolution by natural selection requires heritable variation within a population, and for this variation to influence survival. To understanding cancer evolution, then, we must: determine what generates diversity within tumours, evaluate how extensive this diversity is; distinguish between functional and non-functional diversity; and consider these factors in the context of the environment in which cancer evolution occurs. In this talk, I will outline how we can exploit sequencing data to decipher cancer evolutionary histories. I will explore the importance of large-scale genomic events, including whole genome doubling, in shaping cancer evolution. I will consider how we can use bioinformatics tools to shed light on the interface between the cancer cell and the immune microenvironment, and mechanisms of immune escape. *** Anya Plutynski <https://philosophy.wustl.edu/people/anya-plutynski> (Washington University, USA, via Zoom) *Whither Philosophy of Cancer? Four Open Questions * Philosophical work on cancer is relatively new. In this talk, I raise and provide preliminary answers to four open questions that should be of broad interest to any scholars with interests in this area: First, what tools are relevant to philosophy of cancer, or required to do philosophical work on cancer well? What needs to be invented? What can be adapted from other domains? Second, how can philosophical work on cancer contribute to philosophy more generally, or philosophy of science, in particular? Third, what is the larger agenda of philosophical work on cancer (i.e., beyond philosophy)? I.e., How can or should work on philosophy of cancer contribute to domains outside of philosophy? What role can or should philosophers play in engaging cancer researchers, whether in clinical oncology, epidemiology, or public health? How can or should philosophers contribute to the conversation with cancer patients, families and communities affected by cancer? Fourth and last, what are the major challenges facing current research? Where does philosophical work on cancer need to go next? *** Eric Solary <https://www.gustaveroussy.fr/fr/eric-solary> (INSERM U1287, Institut Gustave Roussy / Université Paris-Saclay, Villejuif, France) What is the roadmap of early tumor development? Cancer is commonly seen as a consequence of somatic evolution in which driver mutations accumulate in a cell, typically a stem or a progenitor cell. Most of these mutations (1-10 per cell division) are neutral passenger events, with only rare variants being potentially advantageous driver mutations in oncogenes and tumor suppressors. Contrary to germ cells, most somatic cells tolerate these potentially toxic alterations with a near complete absence of negative selection. The forces that subsequently promote tumor growth, progression and relapse are typically fuel by genetic and epigenetic diversification. The recent demonstration that evolution of positively selected, genetically modified clones harboring common cancer driver gene mutations in a given tissue does not necessarily imply the presence of cancer in this tissue has blurred our understanding of cancer emergence mechanisms. The frequency of some driver mutations is much higher in normal tissue than in cancer, suggesting that corresponding clones may not necessarily be destined for evolution to cancer and could even negatively select for carcinogenesis. The accumulation of these clones in healthy tissues throughout life and their emergence promoted by chronic inflammation and lifestyle-related toxic insults negatively affect tissue function. The reasons why one of these clones becomes an overt malignant tumor while the others do not in a given tissue remain challenging, which limits our ability to accurately prevent cancer development and detect early-stage cancers. We need a new roadmap of early tumor development, from a mutated but phenotypically normal cell to an invasive malignancy through localized tumor promoting events that may not always involve mutagenic processes. The increased number of mutated clones in ageing and chronically inflamed tissues interrogates the way we could stop cancer before it starts and interrogates the impact of rejuvenating or interception strategies eradicating non-malignant clones in healthy tissues to preserve the tumor suppressive properties of healthy tissues and decrease the risk of cancer development. The computational analysis of single-cell multi-omics and images collected longitudinally from a number of patients and patient-derived experimental models during the progression from health to disease may allow establishing an atlas of pre-neoplastic lesions and cells to guide an interceptive medicine applied to the eradication of early-stage cancers with otherwise lethal potential. We may also decipher the negative impact of specific ecosystems, including individual (genetic, epigenetic) and collective (chemicals, pathogens, radiations) ecosystems, on cancer emergence to generate innovative strategies that improve disease prevention. Invited speakers Bertrand Daignan-Fornier <http://www.ibgc.u-bordeaux2.fr/?page=equipe&eq=grm> (Institute for Genetics and Cell Bilogy, IBGC, CNRS & Univ. Bordeaux, France) (Genetics, multicellularity and cancer) Cancer and multicellularity: general ideas and an experimental approach Multicellularity is a precondition to cancer, but, is cancer a breakdown of multicellularity? Current answers to this question schematically vary from cancer being a partial loss of cooperation, to cancer being a full way back to unicellularity. Those diverse answers lead to very different hypotheses on the origin of the disease and its overall raison d’être. Primarily, this debate questions the nature of multicellularity, the conditions of its emergence and maintenance, and how cancer interferes with these processes. To move along further in this debate, it would be helpful to be able to tackle experimentally the relationship between multicellularity and cancer. One way to do it would consist in asking: do cancer promoting conditions disfavor multicellularity? And if yes how? This could be done by comparing the effects of cancer promoting conditions on uni- and multicellular organisms otherwise as genetically similar as possible. However, multicellularity, as we know it, emerged a long time ago and there are no direct ways to conclusively compare unicellular and multicellular organisms that have evolved independently of each other for millions of years. To circumvent these issues, we are setting up an experimental approach based on synthetic biology on a yeast model that will allow us to compare ‘isogenic’ uni- and multicellular derivatives confronted to conditions that are known to promote cancer. Advantages and limits of the model will be discussed. *** Mathieu Giraudeau <https://lienss.univ-larochelle.fr/Giraudeau-Mathieu> (LIENSs, CNRS & Univ. La Rochelle, France) (Cancer and evolution) 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. These findings will have huge potential to be translated to human patients through evolutionary medicine. 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. *** Fridolin Gross <https://www.immuconcept.org/team_member/fridolin-gross/> (ImmunoConcept, CNRS & Univ. Bordeaux, France) *Cancer and Complexity* What do biomedical researchers mean when they say that cancer is complex? Often what they mean is that cancer is a group of diseases that have defied efforts to cure or control. In this case, “complexity” does not refer to an intrinsic property of any particular object, but rather to a biomedical (or societal) problem. In some cases, however, what is meant is that a particular instance of cancer can be understood as a complex system. Such claims can in turn be interpreted in various ways, and it is not clear whether the implied notion of complexity actually accomplishes anything useful. To better understand the potential role of “complexity” in the context of cancer, I will attempt to place it within the general conceptual framework of biological complexity that I have recently developed. This framework applies the technical notion of “effective complexity” to descriptions of phenomena and their underlying mechanisms, and establishes a spectrum between two extremes that I call “emergent complexity” and “mechanical complexity,” respectively. This conceptual work is useful in particular because the prospects of particular strategies for understanding and managing it may depend on where cancer falls on this spectrum. *** Lucie Laplane <https://www.pantheonsorbonne.fr/page-perso/llaplane> (IHPST, CNRS & Univ. Panthéon-Sorbonne; Gustave Roussy, France) (Philosophy of cancer: clonality) *Revisiting the clonal evolution model* Tumors are made up of heterogeneous cells. This heterogeneity makes cancer cells difficult to target and contributes to therapeutic avoidance and relapses. The clonal evolution model describes the dynamical processes of emergence, growth, decline or disappearance of clones constituting a tumor in space and time. Understanding these dynamics helps avoiding certain pitfalls (such as the selection of resistant clones) and lead to innovative therapeutic strategies taking these dynamics into account, such as adaptive therapies. However, the very concept of a clone is more ambiguous than it appears. I will start by showing that the notion of clone is necessarily relative (relating to the choice of traits used to identify and track clones), that its use is polysemous, and that the traditional conception of the clone is no longer in line with the data, nor with the emerging tools available to study clonal evolution. These mismatches might infringe scientific and clinical progress. A conceptual shift is thus needed to overcome these obstacles, and I will propose some solutions to both clarify the concept and make it more operational. *** Maël Lemoine <https://www.immuconcept.org/team_member/mael-lemoine/> (ImmunoConcept, CNRS & Univ. Bordeaux, France) *** Thomas Pradeu <https://www.immuconcept.org/team_member/thomas-pradeu/> (ImmunoConcept, CNRS & Univ. Bordeaux, France) How does “extended immunity” impact the dialogue between cancer and the immune system? *** Rodrigue Rossignol <http://cvscience.aviesan.fr/cv/560/rodrigue-rossignol> (INSERM & Univ. Bordeaux, France) (Cancer & metabolism) Mitochondria in cancer: a malignant symbiosis? *** Isabelle Sagot <http://www.ibgc.u-bordeaux2.fr/?page=equipe&eq=sagot> (Institute for Genetics and Cell Bilogy, IBGC, CNRS & Univ. Bordeaux, France) On a definition of cellular quiescence For a long period, cellular quiescence was considered as a “sleeping” inactive default state with a poorly acknowledged biological relevance. Yet, an increasing amount of literature is progressively revealing that quiescence is central in many biological processes, such as organism development or tissue maintenance and for major human pathologies such as cancer. In fact, cellular quiescence is captivating, as it is diverse and multifaceted. But, by the way: what is a quiescent cell? *** Bernhard Strauss <https://www.researchgate.net/profile/Bernhard-Strauss-2> (Univ. Cambridge, Department of Biochemistry, UK) “Rethinking Cancer” – when are we done? How conceptual progress in explaining cancer might inform research practice and novel treatment approaches Despite the persistent dominance of the somatic mutation paradigm in current experimental and therapeutic approaches, alternative conceptual frameworks are being increasingly considered and applied in basic and clinical cancer research. In addition, the systematic study of the theoretical underpinnings of cancer research over the past decade by philosophers of science has greatly enhanced and clarified our understanding of the role of theory in this field. However, this has also led to the view that various conceptual frameworks that support different research programs would be equally valid in dealing with the complex biological phenomenon that cancer is. Such a stance of conceptual relativism or perspectivism, will most likely fail to guide innovation in experimental and therapeutic practice in a constructive manner. I propose here that the recent convergence of conceptual innovations and of results in basic and clinical research clearly point toward several gaps in our mechanistic understanding of cancer that can be well defined, and need addressing at the tissue and organism levels to make more progress with therapy. Sincerely, Thomas Pradeu CNRS Research Professor in Philosophy of Science Immunology Unit ImmunoConcEpT, UMR5164, CNRS & University of Bordeaux Stanford University CASBS Fellow <https://casbs.stanford.edu/people/current-fellows> (2020-2021) Team Leader Conceptual Biology and Medicine Team <https://www.immuconcept.org/conceptual-biology-medicine/> PI ERC Starting Grant Immunity, Development, and the Microbiota <http://erc-idem.cnrs.fr/>(2015-2020) Coordinator of the Institute for Philosophy in Biology and Medicine <https://www.philinbiomed.org/> (PhilInBioMed) <https://link.springer.com/journal/10539> 146 rue Leo Saignat 33076 Bordeaux, France & IHPST <https://www.ihpst.cnrs.fr/en> Pantheon-Sorbonne University 13 rue du Four, 75006 Paris, France -- https://www.vidal-rosset.net/mailing_list_educasupphilo.html
