Fourth Philosophy of Cancer Biology Workshop

Telomeres, Cancer and Aging

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.

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.

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 (Institute for Genetics and Cell Biology, 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.

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Mathieu Giraudeau (LIENSs, CNRS & Univ. La Rochelle, France) (Cancer and evolution)

Wildlife species as a source of inspiration in our fight against cancer? (Canceled)

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.

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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.

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Lucie Laplane (IHPST, CNRS & Univ. Panthéon-Sorbonne; Gustave Roussy, France) (Philosophy of cancer: clonality)

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Maël Lemoine (ImmunoConcept, CNRS & Univ. Bordeaux, France)

What does it mean to say that ‘aging causes cancer’?

It is often claimed that ‘aging causes cancer’ and that a good strategy to prevent or cure cancer is to target some processes of aging (the ‘geroscience’ agenda). Yet the meaning of the initial claim is unclear. This is because aging and cancer are understood alternatively in interaction (what they cause to one another) and in extension (what they share with one another). Instead, I propose to investigate whether organismal senescence, the general property of organisms that age as opposed to those that don’t, is a necessary condition for cancer to be possible. This requires first to question the received view that cancer and ‘successful aging’ simply are opposite trajectories: indeed, what is to be understood, is why exactly cancer becomes possible, in most cases, only after an organism has “aged” enough, and whether this indeed makes it a necessary condition. ‘Organismal senescence’ could be characterized as a drift in tissue homeostasis rather than by the passive accumulation of damage. Then, I show that as far as we know, only senescent animals (i.e., bilaterians) can have cancer, but that it requires a specific form of organismal senescence for cancer to be possible, as some senescent organisms never (C. elegans) or rarely (naked-mole rat) have cancer. In the end, I propose a short reinterpretation of the hot topics of cancer geroscience in the light of this new conceptual framework.

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Thomas Pradeu (ImmunoConcept, CNRS & Univ. Bordeaux, France)

What is the immune system of oncoimmunology?

The field of cancer immunology is thriving, with major empirical and clinical results. Yet it is built on a relatively traditional conception of the immune system. In this talk, I show how recent reconceptualizations and extensions of immunity may prompt a new and much richer understanding of the interactions between cancer and the immune system.

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Rodrigue Rossignol (INSERM & Univ. Bordeaux, France) (Cancer & metabolism)

Mitochondria in cancer: a malignant symbiosis?

Our INSERM laboratory investigates the regulation of energy metabolism in physiology and pathology. In particular, the multi-omic molecular analysis of the metabolic reprogramming of human lung tumors revealed novel mechanisms of bioenergetic regulation. More specifically, we identified two subgroups of human lung adenocarcinomas reflected in the histologically normal-paired cancer-adjacent tissue: high (OX⁺) mitochondrial respiration and low (OX^–) mitochondrial respiration. Then, we provided proof-of-concept data for preclinical precision bioenergetic medicine of oxidative lung carcinomas. Additional work demonstrated that tobacco-specific nitrosamines activate mitochondrial redox signalling to promote lung tumor growth. These malignant properties were acquired by the upregulation and activation of the beta-adrenergic receptor (β2-AR)-nicotinic acetylcholine receptor subunit alpha-7 (CHRNAα7)-dependent nitrosamine canonical signalling pathway. Altogether, our findings provide knowledge in the field of metabolic regulation, REDOX biology and human lung cancer bioenergetics with medical implication for cancer diagnosis and treatment.

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Isabelle Sagot (Institute for Genetics and Cell Bilogy, IBGC, CNRS & Univ. Bordeaux, France)

Bernhard Strauss (Univ. Cambridge, Department of Biochemistry, UK)