2019-01547 - PhD Position F/M Modeling the drug response heterogeneity to cancer drugs by cell-to-cell synchronization and feedback in the cell death signaling cascade
Le descriptif de l’offre ci-dessous est en Anglais

Type de contrat : CDD de la fonction publique

Niveau de diplôme exigé : Bac + 5 ou équivalent

Fonction : Doctorant

A propos du centre ou de la direction fonctionnelle

The Inria Sophia Antipolis - Méditerranée center counts 37 research teams and 9 support departments. The center's staff (about 600 people including 400 Inria employees) is composed of scientists of different nationalities (250 foreigners of 50 nationalities), engineers, technicians and administrators. 1/3 of the staff are civil servants, the others are contractual. The majority of the research teams at the center are located in Sophia Antipolis and Nice in the Alpes-Maritimes. Six teams are based in Montpellier and a team is hosted by the computer science department of the University of Bologna in Italy. The Center is a member of the University and Institution Community (ComUE) "Université Côte d'Azur (UCA)".

Contexte et atouts du poste

Initiation of apoptosis (cell death) is a critical cellular decision in tissue homeostasis and cancer emergence. However, a wide range of variability is observed in cell populations, where even identical sister cells can exhibit a considerable degree of heterogeneity in response to equal drug treatments.

Recent work by Roux et al [1], uses single cell measurements to show the diversity of cell responses to death ligand drugs within a clonal population of cells: some cells commit to cell death, while others survive. These findings have a particular significance in the cancer research field, by revealing how resistance to death receptor ligands can simply arise from cell-to-cell heterogeneity within a genetically-identical cell population and contribute to the tumor growth relapse.

The main objective of this thesis is to investigate biomolecular mechanisms that may generate a wide variability in cellular response to death ligands, using mathematical modeling, parameter estimation, and model analysis. The work will be developed within a collaboration between Jeremie Roux, at the Institute for research on cancer and aging (Ircan, Nice), and Madalena Chaves at Biocore, Inria.

Together with the candidate, we will apply for an Inria-Inserm fellowship in numerical medecine.

References:
[1] J. Roux, M. Hafner, S. Bandara, J.J. Sims, H. Hudson, D. Chai, and P. Sorger. Fractional killing arises from cell‐to‐cell variability in overcoming a caspase activity threshold. Molecular System Biology, 11(5), 803, 2015.

 

 

Mission confiée

In this context, a mathematical model based on mass-action kinetics has recently been developed, to represent a cascade of molecular events from the activation of specific death receptors to caspase 8 signaling which leads to apoptosis commitment. This model was fitted to a set of experimental single-cell trajectories to obtain a family of parameter sets that represent the variability within the cell population.

Based on this first model, the thesis project will develop two new directions:

(i) Inter-cellular communication and synchronization. To investigate the effect of cell-to-cell exchanges in the variability of cell responses, we will study a network composed of similar interacting cascades, connected by an appropriate coupling scheme. Depending on the scheme and strength of the coupling, the composed network may exhibit new dynamical behaviors; we will analyze mathematical conditions for cell synchronization or, conversely, conditions leading to novel patterns of heterogeneity in cell response. These modeling and simulation results will be compared to single cell data from different experimental setups, which allow or prevent inter-cellular communications.

(ii) Feedbacks from downstream events. The reactions initiated with death ligand-receptor binding trigger a number of signaling pathways and downstream events, ending with the differential regulation of sets of genes. Here, we will investigate possible feedbacks into the main caspase 8 cascade, from signaling pathways activated in parallel or specific regulatory proteins. In particular, we will study the effect of feedback loops in the dynamical behavior of caspase 8 signaling. The objective is to analyze the variations induced by a feedback loop in the properties of the caspase 8 response dynamics and compare these to the experimentally observed variability.

In a close alliance between mathematical analyses and experimental data, based on modeling, parameter estimation and analysis, the current project will thus focus on studying, interpreting, and better understanding cell heterogeneity data in tumor cells.

 

Principales activités

Mathematical modeling and analysis of the system, by application of different techniques from Dynamical Systems and Control.

Numerical simulations and analysis.

Writing a report/paper on the results.

Present and communicate the results at a workshop, conference, etc.

Compétences

The candidate should have a background in applied mathematics, dynamical systems or similar areas.

The candidate should be proficient in the english language (reading/speaking/listening).
The candidate should master some computer languages and programming software (eg., Linux, C, scilab, matlab, ...)

Avantages

  • Subsidized meals
  • Partial reimbursement of public transport costs
  • Leave: 7 weeks of annual leave + 10 extra days off due to RTT (statutory reduction in working hours) + possibility of exceptional leave (sick children, moving home, etc.)
  • Possibility of teleworking (after 6 months of employment) and flexible organization of working hours
  • Professional equipment available (videoconferencing, loan of computer equipment, etc.)
  • Social, cultural and sports events and activities
  • Access to vocational training
  • Social security coverage

Rémunération

Duration: 36 months
Location: Sophia Antipolis, France
Gross Salary per month: 1982€brut per month (year 1 & 2) and 2085€ brut/month (year 3)