PDF e-Pub

## Section: Application Domains

### Applicative axis 1: Focus on cancer

Personnel

Luis Almeida, Jean Clairambault, Marie Doumic, Dirk Drasdo, Benoît Perthame, Diane Peurichard, Nastassia Pouradier Duteil.

Project-team positioning

The MAMBA team designs and analyses mathematical models of tumor growth and therapy, at the cell population level, using agent-based or partial differential equations, with special interest in methodologies for therapeutic optimization using combined anticancer drug treatments. Rather than, or not only, modeling the effect of drugs on molecular targets, we represent these effects by their functional consequences on the fate of healthy and cancer cell populations: proliferation (velocity of the cell division cycle, decreasing it, e.g., by antagonizing growth factor receptors), apoptosis, cell death or senescence. Our goal in doing this is to circumvent the two main issues of anticancer therapy in the clinic, namely unwanted toxic side effects in populations of healthy cells and emergence of drug-induced drug resistance in cancer cell populations. This point of view leads us to take into account phenomena of transient and reversible resistance, observed in many cancer cell populations, by designing and analyzing models of cell populations structured in continuous phenotypes, relevant for the description of the behavior of cell populations exposed to drugs: either degree of resistance to a given drug, or potential of resistance to drug-induced stress, proliferation potential, and plasticity. Such modeling options naturally lead us to to take into account in a continuous way (i.e., by continuous-valued phenotype or relevant gene expression) the wide phenotypic heterogeneity of cancer cell populations. They also lead us to adopt the point of view of adaptive dynamics according to which characteristic traits of cell populations evolve with tumor environmental pressure (drugs, cytokines or metabolic conditions, mechanical stress and spatial conditions), in particular from drug sensitivity to resistance. This position is original on the international scene of teams dealing with drug resistance in cancer.

Scientific achievements

Modeling Acute Myeloid Leukemia (AML) and its control by anticancer drugs by PDEs and Delay Differential equations

In collaboration with Catherine Bonnet (Inria DISCO, Saclay) and François Delhommeau (St Antoine hospital in Paris), together with DISCO PhD students José Luis Avila Alonso and Walid Djema, this theme has led to common published proceedings of conferences: IFAC, ACC, CDC, MTNS  [66], [67], [68], [77], [95], [65]. These works study the stability of the haematopoietic system and its possible restabilization by combinations of anticancer drugs with functional targets on cell populations: proliferation, apoptosis, differentiation.

Adaptive dynamics setting to model and circumvent evolution towards drug resistance in cancer by optimal control

We tackle the problem to represent and inhibit - using optimal control algorithms, in collaboration with Emmanuel Trélat, proposed Inria team CAGE - drug-induced drug resistance in cancer cell populations. This theme, presently at the core of our works on cancer modeling with a evolutionary perspective on tumor heterogeneity, is documented in a series of articles  [90], [92], [124], [125], [127]. Taking into account the two main pitfalls of cancer therapy, unwanted side effects on healthy cells and evolution towards resistance in cancer cells, it has attracted to our team the interest of several teams of biologists, with whom we have undertaken common collaborative works, funded by laureate answers to national calls (see ITMO Cancer HTE call).

This theme is also at the origin of methodological developments (see Research axis 1). In collaboration with Shensi Shen from Institut Gustave Roussy and Francois Vallette from Université de Nantes, we aim to develop simple non-spatial models to understand the mechanisms of drug resistance acquisition -and loss- in melanoma and glioblastoma. The models are systematically compared with in vitro and in vivo data generated by our collaborators and treated via image processing techniques developed in the team.

Senescence modeling by telomere shortening

In many animals, aging tissues accumulate senescent cells, a process which is beneficial to protect from cancer in the young organism. In collaboration with Teresa Teixeira and Zhou Xu from IBCP, we proposed a mathematical model based on the molecular mechanisms of telomere replication and shortening and fitted it on individual lineages of senescent Saccharomyces cerevisiae cells, in order to decipher the causes of heterogeneity in replicative senescence  [79].

Biomechanically mediated growth control of cancer cells

Model simulations indicate that the response of growing cell populations on mechanical stress follows a simple universal functional relationship and is predictable over different cell lines and growth conditions despite the response curves look largely different. We developed a hybrid model strategy in which cells were represented by coarse-grained individual units calibrated in a high resolution cell model and parameterized each model cell by measurable biophysical and cell-biological parameters. Cell cycle progression in our model is controlled by volumetric strain, the latter being derived from a bio-mechanical relation between applied pressure and cell compressibility. After parameter calibration from experiments with mouse colon carcinoma cells growing against the resistance of an elastic alginate capsule, the model adequately predicts the growth curve in i) soft and rigid capsules, ii) in different experimental conditions where the mechanical stress is generated by osmosis via a high molecular weight dextran solution, and iii) for other cell types with different growth kinetics. Our model simulation results suggest that the growth response of cell population upon externally applied mechanical stress is the same, as it can be quantitatively predicted using the same growth progression function [123].

Bio-mechanical models of tissue growth

The degenerate Cahn-Hilliard equation is a standard model to describe living tissues. It takes into account cell populations undergoing short-range attraction and long-range repulsion effects. In this framework, we consider the usual Cahn-Hilliard equation with a singular single-well potential and degenerate mobility. These degeneracy and singularity induce numerous difficulties, in particular for its numerical simulation. To overcome these issues, we propose in [hal-02274417] a relaxation system formed of two second order equations which can be solved with standard packages. This system is endowed with an energy and an entropy structure compatible with the limiting equation. Here, we study the theoretical properties of this system; global existence and convergence of the relaxed system to the degenerate Cahn-Hilliard equation. We also study the long-time asymptotics which interest relies on the numerous possible steady states with given mass.

Free boundary multiphase models of tumor growth

Multiphase mechanical models are now commonly used to describe living tissues including tumour growth. The specific model we study here consists of two equations of mixed parabolic and hyperbolic type which extend the standard compressible porous media equation, including cross-reaction terms. We study the incompressible limit, when the pressure becomes stiff, which generates a free boundary problem. We establish the complementarity relation and also a segregation result. Several major mathematical difficulties arise in the two species case which are addressed in [43]. Firstly, the system structure makes comparison principles fail. Secondly, segregation and internal layers limit the regularity available on some quantities to BV. Thirdly, the Aronson-Bénilan estimates cannot be established in our context. We are lead, as it is classical, to add correction terms. This procedure requires technical manipulations based on BV estimates only valid in one space dimension. Another novelty is to establish an ${L}^{1}$ version in place of the standard upper bound.

Philosophy of cancer

The quite natural idea that cancer is a disease of the control of coherent multicellularity, expressed when cohesion of tissues and coherence of (unknown, except maybe for the case of a centralised circadian clock) synchronising signals fail to ensure it, by a regression towards unicellularity, stopping in this “reverse evolution path” at a coarse, incoherent multicellularity state  (Metazoa 1.0, as theorised by PCW Davies and CH Lineweaver in their article “Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors”, Physical Biology 2011, that popularised the so-called atavistic hypothesis of cancer) continues to be developed and popularised by Jean Clairambault in seminars and workshops, and published in review articles [13], [45]. This view, and the investigation of the immune system in the design of such coherence of all multicellular organisms  (this latter point partly, however nicely, developed in Thomas Pradeu's book “The limits of the self”, OUP 2012) is naturally inscribed in a philosophy of cancer perspective, and from a mathematical viewpoint, to multicellularity genes - and links between them and unicellularity genes - seen as a hyperstructure  (See on this point, e.g., Nils Baas: “On the philosophy of higher structures”, Int. J. General Systems 2019) above structures consisting of the genes of unicellularity, i.e., those that make a single cell a coherent living system, such hyperstructure being failed in cancer; this view is presently under development with colleagues from universities of the Paris region, together with Nils Baas at NTNU, Trondheim, Norway). This perspective, that makes use of category theory as a structuring point of view to apprehend multicellularity and cancer, is also meant to endow us with an innovative methodology to apply topological data analysis (TDA) to investigate cancer genome data.

Modelling of TMZ induced drug resistance

Temozolomide (TMZ) is a standard chemotherapy treatment in patients with glioblastoma. Resistance to this drug is correlated to the presence of a specific enzyme, which activity in cancer cells creates a drug-induced cell death resistant phenotype. Understanding the transition of cancer cells to a resistant phenotype is still a topic of research where multiple hypothesis have been studied: From an adaptive process to an inherent resistance to treatment. Moreover it has been recently shown that TMZ treatment has an influence on the spatial structuration of cancer cell aggregates. In the frame of the HTE project MoGlImaging and through the recent hiring of a post-doctoral candidate (Gissell Estrada Rodriguez), we are currently developping a mathematical framework to study and analyse the evolution of a population of glioblastoma cells that are exposed to TMZ. Based on the experimental data generated by our partner team led by F. Valette (Inserm Nantes), we propose a Keller-Segel type model for the formation of spheroid as a result of a chemoattractant produced by cancer cells, and study the influence of a chemotherapeutic agent on the structuration of the cancer cell aggregates. By confronting the model results to experimental data, different modelling choices are currently explored to identify which key mechanisms could be responsible for the apparition of drug resistance in glioblastoma.

Collaborations

• AML modelling: Catherine Bonnet, DISCO Inria team, Saclay, and François Delhommeau, INSERM St Antoine (also collaborator in the INSERM HTE laureate project EcoAML, see below).

• INSERM HTE laureate project MoGlImaging, headed by E. Moyal (Toulouse): François Vallette, CRCNA and INSERM Nantes

• INSERM HTE laureate project EcoAML, headed by François Delhommeau, INSERM St Antoine: François Delhommeau, Thierry Jaffredo (IBPS), Delphine Salort (LCQB-IBPS)

• Adaptive dynamics to model drug resistance and optimal control to circumvent it:

Alexandre Escargueil, Michèle Sabbah (1 PhD thesis in common), St Antoine Hospital, Paris

Emmanuel Trélat (1 PhD thesis in common) at Inria team CAGE and Laboratoire Jacques-Louis Lions at Sorbonne Université.

Frédéric Thomas at CREEC, Montpellier.

Tommaso Lorenzi (Univ. of St Andrews).

• Telomere shortening: Teresa Teixeira and Zhou Xu (IBCP, Paris), Philippe Robert (Inria RAP).

• TRAIL treatment: Gregory Batt, Inria Saclay and Inst. Pasteur (France)

• Biomechanical control of cancer cells: Pierre Nassoy, Bioimaging and Optofluidics Group, LP2N – UMR 5298. IOGS, CNRS & University of Bordeaux