Third Philosophy of Cancer Biology Workshop, with Fanny Jaulin and Andrei Seluanov (via Zoom)

 

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Videos of talks available below

 

Program and list of speakers

Program 3rd Philosophy of Cancer Biology Workshop (please click to enlarge)

Plenary speakers

Fanny Jaulin (Gustave Roussy, INSERM, France) – Cell biology to learn from and fight against cancer

Andrei Seluanov (University of Rochester, USA) – Novel tumor suppressor mechanism in long lived mammals

 

Invited speakers

Pierre Soubeyran (Unicancer, Bordeaux, France)– Streamlined Geriatric and Oncological evaluation based on IC Technology for holistic patient-oriented healthcare management for older multimorbid patients. The GerOnTe project.

Laurent Cognet (LP2N – Institut d’Optique, Bordeaux, France)– A physicist attempt to help the field of cancer research: building new tools for analyzing the tumor microenvironment.

Vanja Sisirak (Immuno-ConcEpT, Bordeaux, France)– Regulation of tumor-derived DNA potential to activate anti-tumor immune responses by extracellular DNases

Sara Green (University of Copenhagen, Denmark)– Cancer Avatars: The Temporality of Translation in Precision Oncology 

Macha Nikolski (CBiB, Bordeaux, France)– Computational analysis of cancer genomes

Sarah Yvonnet (Sorbonne Université, Paris, France)– Dealing with complexity in cancer therapeutic field

Marie Darrason (Centre Hospitalier Lyon Sud- Hospices Civils de Lyon, France)– Detecting (and treating?) cancer without a visible disease? Some epistemological issues underlying cancer screening through liquid biopsies

Violaine Moreau (INSERM, Bordeaux, France)– Deciphering the dual role of ß-catenin in hepatocellular carcinoma

Clémence Guillermain (Université Paris Diderot, Paris, France)– Cancer & Aging: a complex yet scientifically stimulating relationship

 

Videos

– Pierre Soubeyran & Laurent Cognet :

– Sara Green & Fanny Jaulin :

– Macha Nikolski, Sarah Yvonnet & Marie Darrason :

– Clémence Guillermain : 

 

 

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Abstracts

Plenary speakers

Fanny Jaulin (Gustave Roussy, INSERM, France)

Cell biology to learn from and fight against cancer

 

 

Andrei Seluanov (University of Rochester, USA)

Novel tumor suppressor mechanism in long lived mammals​

Cancer researchers have traditionally used the mouse and the rat as staple model organisms. These animals are very short-lived, reproduce rapidly, and are highly prone to cancer. They have been very useful for modeling some human cancer types and testing experimental treatments; however, these cancer-prone species offer little for understanding the mechanisms of cancer resistance. Recent technological advances have expanded research bestiary to non-standard model organisms that possess unique traits of very high value to humans such as cancer resistance and longevity. In recent years, several discoveries have been made in non-standard mammalian species providing new insights on the natural mechanisms of cancer resistance. These include mechanisms of cancer resistance in the naked mole rat, blind mole rat and elephant. In each of these species, evolution took a different path leading to novel mechanisms. Many other long-lived mammalian species display cancer resistance, including whales, grey squirrels, microbats, cows and horses. Understanding the molecular mechanisms of cancer resistance in all of these species is important and timely as ultimately, these mechanisms could be harnessed for the development of human cancer therapies.

 

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Invited speakers

Pierre Soubeyran (Unicancer, Bordeaux, France)

Streamlined Geriatric and Oncological evaluation based on IC Technology for holistic patient-oriented healthcare management for older multimorbid patients. The GerOnTe project.

Population is aging and the number of complex multimorbid patients to manage will increase sharply. Disease-centred approach is not appropriate to manage these patients. Change to a patient-centred approach will simplify care pathways, secure management and treatment decision making and decrease healthcare costs. It will be a real breakthrough for daily practice with multiple impacts that must be quantified. GERONTE multimorbid patient-centred system proposes: 1) Coordination of management by a patient-tailored, interdisciplinary health professional consortium (HPC), including hospital- and home-based professionals, with a case manager; 2) Timely registration of symptoms and patient-reported outcomes at home through a web-based app for anticipation of avoidable adverse events; 3) Proposal of self-management guidelines according to intrinsic capacity evaluation by geriatrician for patient-driven improvement of independent living; 4) Structured collection of data from electronic health record into a dashboard made available to HPC members as well as patient and caregiver, thanks to its capacity to securely interoperate with all electronic health records including software managing medical data. The whole approach will be co-designed with patients, informal care givers and health professionals. Cancer is an excellent model to develop this approach in multimorbid patients because it is frequent and commonly associated with other morbidities in older patients but also because of its major impact on patients’ general status and coexistent diseases. Cancer already benefits from a multidisciplinary management model that GERONTE will enhance, strengthening exchange of holistic data, role of primary care and case management. GERONTE will also provide new country-specific guidelines and best practices for implementation across Europe and for mproved management of older multimorbid patients including improved quality of life and independent living at decreased costs.

 

Laurent Cognet (LP2N – Institut d’Optique, Bordeaux, France)

A physicist attempt to help the field of cancer research: building new tools for analyzing the tumor microenvironment.

Single-molecule localization microscopy (SMLM) is the ultimate approach to study structural and dynamic arrangements of the matter at the nanoscale in a wide range of applications. As a member of the “super-resolution microscopy” family SMLM indeed provides optical images with resolutions well beyond the diffraction limit and allow the behavior of one single molecule to be deciphered among other ones. Yet, it remains challenging to study more complex systems than isolated nanostructures or isolated living cells in biology with such approaches. For instance, SMLM in thick tissues (e.g. in situ tumors, or biopsies) is penalized by the limited brightness of fluorescent emitters, the optical aberrations induced by the samples and/or the poor penetration of the light into biological tissue at visible wavelengths.

To circumvent these limitations, we recently developed several new schemes. I will focus here on approaches based on single carbon nanotube which strongly emit in the near-infrared [1]. Combining SMLM and carbon nanotube microscopy, we obtained nano-resolved maps of the extracellular space within intact live brain tissues [2] and in the context of neurodegenerative diseases [3]. We believe that such approaches can be transferable to the fine exploration of the tumor microenvironment. In this quest we are also developing a novel family of multicolor nanoprobes that can be engineered for ultrasensitive microscopy in the near-infrared [3] and might therefore be of great interest for diagnostic purposes based on the analysis of biopsies.

[1] Fakhri, et al Science (2010), Danné, et al ACS Photonics (2018)

[2] Godin, et al Nat. Nanotechnol. (2017)

[3] Soria et al Nat. Commun. (2020)

[4] Danné et al, ACS Nano, (2018), Godin, et al Adv. Science (2019)

Vanja Sisirak (CNRS-UMR 5164, Immuno-ConcEpT, Bordeaux, France)¹

Regulation of tumor-derived DNA potential to activate anti-tumor immune responses by extracellular DNases

Anne Garreau¹, Pauline Santa¹, Amandine Ferriere¹, and Vanja Sisirak¹

The current wave of immunotherapy has demonstrated a strong therapeutic impact for cancer patients. The major modalities gaining broad clinical applicability aim at blocking regulatory pathways silencing the immune system within tumors called “immune checkpoints”. However, a minority of patients (~30-40%) respond to such treatment stressing the importance of understanding mechanisms regulating anti-tumor immune responses. The sensing of tumor-derived DNA by tumor-infiltrating dendritic cells and macrophages was shown to play a critical role in type I interferon (IFN-I) production which is essential for the activation of cytotoxic lymphocytes that ultimately eliminate tumors. While the majority of tumor cells release DNA, not all patients show an IFN-I signature and a spontaneous T cell-mediated anti-tumor immunity, suggesting that tumor-derived DNA immunogenicity is tightly regulated. We have characterized a nuclease called DNASE1L3 that plays a critical role in the regulation of immunogenic self-DNA by restricting DNA length and reducing its exposure on microparticles derived from apoptotic cells, thereby preventing its capacity to stimulate immune responses. Given these DNASE1L3 properties and its high expression in tumor-infiltrating dendritic cells and macrophages, we hypothesized that the DNASE1L3 within the tumor microenvironment may regulate tumor-derived DNA immunogenicity and consequently anti-tumor responses. We observed that DNASE1L3 deficiency in spontaneous and transplantable mammary tumor models did not affect neither tumor growth nor spontaneous anti-tumor immune responses. However, DNASE1L3 deficiency prevented the therapeutic impact of a common immunogenic chemotherapy Doxorubicin. These results suggest that the DNASE1L3 in the tumor context may not only play a role in disposing of DNA but promote tumor DNA-sensing by the innate immune cells, following tumor DNA release caused by chemotherapy. Accordingly, Doxorubicin caused tumor cells death leading to the release of compact and unfragmented DNA. Exogenous treatment by DNASE1L3 of  Doxorubicin treated cells potently increased the fragmentation of their DNA. Thus, DNASE1L3 may process tumor-derived DNA to promote its sensing by innate immune cells. We also have observed that the supernatants of tumor cells treated with Doxorubicin increased the expression of the DNASE1L3 within dendritic cells, supporting the hypothesis that this enzyme is involved in the regulation of anti-tumor immune responses. While DNASE1L3 may regulate the immunogenicity of chemotherapies, we need to further decipher its mechanisms of action in the regulation of dendritic cells and macrophages activation by tumor DNA. Furthermore, we will the study DNASE1L3 function in development anti-tumor immunity following multiple therapeutic context targeting tumor cells death such as immunotherapy and radiotherapy. Ultimately our study will shed light on novel mechanisms regulating immune responses induced by tumor-derived DNA and therefore may contribute to the development of therapeutic strategies to increase anti-tumor immunity.

Sara Green (Section for History and Philosophy of Science, Department of Science Education, University of Copenhagen, Denmark)

Cancer Avatars: The Temporality of Translation in Precision Oncology 

Sara Green, Mie Seest Dam & Mette Nordahl Svendsen

Patient-derived xenografts (PDX) are currently promoted as new translational models in precision oncology. Immunodeficient mice with human tumors are developed as surrogate models to represent specific types of cancer, and are hoped to allow for patient-specific drug screens. This paper reflects on how organism choice intersects with discussions about the most salient features of cancer, as reflected in how model virtues are balanced and traded. This is for instance seen in discussions on the benefits and limitations of PDXs versus standardised mouse models, and in recent attempts to speed up translation through modification and use of faster developing organisms, such as zebrafish xenografts and fly avatars. Whereas discussions on organism choice often focus on representational features of animal models, we stress that temporality is a model virtue that is central to modeling of cancer. 

 

Macha Nikolski (CBiB, Bordeaux, France)

Computational analysis of cancer genomes

Cancer results from the excessive proliferation of cells descending from the same founder cell and following a Darwinian process of diversification and selection. This process is defined by the accumulation of genetic and epigenetic alterations whose characterization is a key element for establishing a therapy that would specifically target tumor cells. The advent of new high-throughput omics technologies enables this characterization at the molecular level. This technological revolution has led to the development of numerous bioinformatics methods.

In this presentation, we will broadly present the field of bioinformatics and discuss the challenges of its position with respect to its “neighboring” disciplines.

We will further cover the heart of our own research that concerns the development of new computational methods for the analysis of high throughput data of tumor samples and an accurate description of tumor subpopulations.

 

Sarah Yvonnet (Sorbonne Université, Paris, France)

Dealing with complexity in cancer therapeutic field

A system can be considered as complex in a variety of ways (Mitchell, 2003, 2008). Cancer is regarded as a complex disease from both a causal and a dynamical point of view. On the one hand, cancer has a complex multifactorial causal network (Nwosu and al., 2001). It involves genetic and epigenetic deregulations, altered cellular signaling responses, and abnormal interactions with the microenvironment. Those alterations are temporally connected in a complex fashion. On the other, tumor cells are submitted to selective pressure, which results in a still more complex dynamics (Mitchell 2003; Germain and Laplane, 2016), especially when treatment encounters acquired resistance (primary resistance being due to the causal complexity of cancer). Both types of complexity threaten therapeutic attempts.
Our purpose is to rely on the above epistemological analysis of cancer complexity to address the question of how physicians should face this two-dimensional complexity. We will focus on a recent and promising class of therapeutics: immunotherapies. Immunotherapy refers to many different therapeutic strategies. We propose to analyse the assumption behind each strategy in order to understand the way clinical field has dealt with both aspects of complexity. We will present a typology of the different immunotherapies regarding the dimension of complexity they address and how.
The main way to deal with biological complexity has been to focus on targeting different causal pathways simultaneously (or according to a precisely determined order) (Green, 2015, 2017). This approach relies on two assumptions: 1) Cancer is a cluster of mutated proliferating cells; 2) Targeting different causal mechanisms is the best way to eradicate this cluster. A key type of mechanisms is the escape from immune surveillance. Strategies have relied on improving our understanding of immune activation. Therapies can use modern technologies such as CAR-T cells or endogenous regulatory factors as IL2. Both strategies broadly activate the immune system without targeting a precisely identified deficiency (Alatrash et al., 2013; Sanmamed et Chen, 2018). However, those unspecific therapies have strong side effects such as avoid immune related adverse events (Sanmamed et Chen, 2018).
Growing accumulation of data and molecular profiles allowed for new insights into causal mechanisms of immune escape. It has led to therapies targeting specific pathways involved in cancer actively inhibiting antitumor immunity (Sanmamed et Chen, 2018). Blockades of immune checkpoints strategies (anti-PD1) restore a previously blocked immune response to increase the antitumor responses.
The previous approach only addresses the causal dimension of cancer complexity. Despite increasing knowledge about cancer causal network that allows for overcoming primary resistance, immune therapies still face the problem of acquired resistance. We will then focus on strategies (Finn, 2018) that address the other dimension of complexity: the dynamic aspect (Germain and Laplane, 2016). This approach puts forward the following assumptions as its main basis for therapeutic action: 1) Cancer is a dynamic systemic process 2) The latest therapeutic strategies intervene, the poorest the prognosis will be (Cohen et al., 2017). They allow for different therapeutic goals: prevention instead of eradication.

 

Marie Darrason (Centre Hospitalier Lyon Sud- Hospices Civils de Lyon, France)

Detecting (and treating?) cancer without a visible disease? Some epistemological issues underlying cancer screening through liquid biopsies

Detecting cancer at its early stage is often considered as the ultimate goal that would help to reduce cancer mortality. Recently, several attempts, based on what is called “liquid biopsies” (blood-based detection of circulating tumor DNA, or of circulating tumor cells), have been suggested. The latest attempt is PanSeer, a blood-based screening test that has been developed in China and is based on the identification of cancer-specific methylation signatures. The authors of the study (Chen et al, Nature Communications, 2020) claim that PanSeer demonstrates the early detection of multiple cancer types (stomach, oesophageal, colorectal, lung or liver cancer) up to four years prior to conventional diagnosis. At this stage of detection, there is usually no visible disease. In this talk, I will discuss the epistemological and ethical issues underlying these different projects of detecting cancer without a visible disease. I have three main concerns: 1) Do these projects fundamentally differ from the usual attempts at screening cancers through biomarkers (the PSA antigen for prostate cancer for example) or through medical imaging techniques (breast cancer screening through mammography)? Or are they just a new step in an old direction? 2) What kind of assumptions about the nature of cancer do underlie these types of projects? 3) And finally, admitting that such projects would become a reality, would it be acceptable to treat these invisible diseases at such an early stage? What would be the practical and clinical applications for physicians and patients?

 

Violaine Moreau (INSERM, Bordeaux, France)

Deciphering the dual role of ß-catenin in hepatocellular carcinoma

Tumor development and progression are mainly driven by oncogenic mutations but are also strongly influenced by physical factors. Indeed, intra- and inter-cellular communications coordinate various cellular activities that direct proliferation and migration through signal transduction pathways. ß-catenin is a key effector of these inside-out and outside-in mechanotransduction events. ß-catenin is part of the cell-cell adhesion complex, where it plays a structural role but is also the key effector of the Wnt pathway, where it is endowed with a transcriptional regulatory activity.
In the liver, deregulation of ß-catenin is tumorigenic. Oncogenic mutations of ß-catenin are present in 18-41% of hepatocellular carcinoma (main primary malignancy of the liver in adults) and almost 90% of hepatoblastoma (pediatric liver primary tumor). In most liver tumors, ß-catenin mutations are present at the heterozygous state meaning that mutated and wild-type alleles co-exist in tumor cells. We aim to study the interplay between mutated and WT ß-catenins in liver tumor cells.
We have devised a RNA interference strategy in HepG2 cells that allows uncoupling of the two functions of ß-catenin in the same cellular background: nuclear/transcriptional activity, a function almost exclusively mediated by the mutated ß-catenin, and membrane/structural activity, which is mediated by the degradable WT ß-catenin.
During this seminar, I will present how this “dual ß-cat HepG2 model” allowed us identify Fascin 1 as a ß-catenin target involved in the deregulation of hepatocyte differentiation.

 

Clémence Guillermain (Université Paris Diderot, Paris, France)

Cancer & Aging: a complex yet scientifically stimulating relationship​

The hypothesis of a link between cancer and aging was initially derived from population studies. Indeed, as cancer incidence and cancer-related mortality both increase exponentially for individuals aged 50 to 85, the relatively recent explosion of cancer prevalence in developed countries is largely explained by the ageing of their populations. However, while the demographic link between ageing and cancer may seem easy to understand, the hypothesis of a biological link between ageing and cancer remains far from being obvious – and yet it appears recurrently in the contemporary scientific literature.

Our approach is, above all, epistemological and conceptual. We would like to start from this hypothesis and to propose a reasoning in three steps. Our whole presentation will be based on a corpus of recent scientific papers that we believe are representative of the contemporary biology of ageing.

First, we will question the exact nature of the link (whether it is real or supposed) between aging and cancer. We will examine four possible answers and will try to identify more specifically, in each case, the main scientific bases underlying them.
Second, we will try to evaluate the value of such a hypothesis for scientific research in general, and for contemporary biology of ageing in particular, by attempting to answer the following question: why (i.e. for what purpose?) is such a large number of articles based on (or simply evoking) the existence of a link between ageing and cancer?
In a third and last part, we will take a more critical approach by trying to identify: (1) the conceptual and normative implications of the hypothesis of a link between cancer and ageing; but also (2) the limits of such a hypothesis, as well as the criticisms that can be made against it.

Overall, we will try to show that the existence of a biological link between cancer and ageing is an interesting scientific hypothesis, because it is both extremely fertile and highly operational; and that this statement is especially true for the biology of ageing. However, we will also highlight the fact that it is and remains essentially a hypothesis, and must therefore be apprehended and manipulated as such, i.e. with great caution and full awareness of its scope and its limits.