Team
Mechanobiology, Immunity and Cancer

Dpt: Microenvironment, cell plasticity and signalling

Our research activities

The team is devoted to the study of cellular integration of various signals coming from the cellular environment by human macrophages. We seek to understand how these innate immune cells cope with various biological, chemical and physical signals from their environment to generate appropriate immune functions. We develop projects using physiological and pathophysiological contexts to understand how this adaptability of the cellular response could be used to decipher the molecular mechanisms involved in various diseases (cancers, chronic inflammatory conditions) and how this knowledge could be used to develop innovative therapeutic strategies targeting human macrophages. This approach lead us to recognize the importance of the 3D physical organization of the extracellular matrix as well as the level of available oxygen as key elements in macrophage’s biology. Supporting this recognition the metabolic activity of macrophages appears as a fundamental element in order to obtain fine-tuning of the innate immune response in various context. The team is developing very complementary approaches to benefit from the immunometabolism study to tackle the goal to obtain controlled macrophage’s reprogramming in pathological situations to restore the hemeostasis of diseased tissues.
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Arnaud MILLET

Team leader

06 66 88 34 82

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Our research axes

In this axis, we develop the molecular exploration of the metabolic processes involved in the response of macrophages toward modifications of their cellular environment by biochemical and physicochemical signals. We notably explore the importance of the control of the pyrimidine metabolism pathway in the global metabolic adaptation of human macrophages to hypoxia.

Benefiting from our discovery that hypoxic macrophages are deeply involved in the resistance to pyrimidine analogues based chemotherapy, we study the implication of macrophages trough their metabolic activity to treatment resistance in various solid cancers. We notably study from a quantitative point of view the link between spatial organization of macrophages in tissues and their involvement in treatment resistance.

In this part of the project, we develop innovative strategies to target specifically the metabolism of macrophages to obtain a therapeutic response. These developments are focused mainly on the targeting of macrophage-driven chemoresistance but also non-cancerous chronic inflammatory conditions. Our strategies are designed to specifically target tissue macrophages as well as circulating human monocytes.

Our research program is based on fundamental questions using approaches from cell biology, immunology and experimental medicine. All the past, current and future research programs developed in the team are designed to generate new scientific knowledge and to offer opportunities to propose relevant medical strategies. In order to fulfil these goals, we develop translational approaches to validate our ideas in in vivo humanized models in mice and in clinical settings with a particular interest in digestive cancers.

Our major publications

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Metabolic reprogramming of hypoxic tumour-associated macrophages through CSF-1R targeting favours treatment efficiency in colorectal cancers

Khaldoun Gharzeddine, Cristina Gonzales Pietro, Marie Malier, Clara Hennot, Renata Grespan, Yoshiki Yamaryo-Botté, Cyrille Y.…

BioRxiv 2024

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Les macrophages associés à la tumeur - De nouvelles cibles pour contrecarrer la chimiorésistance au 5-fluorouracile dans les cancers colorectaux ?

Malier M, Gharzeddine K, Laverriere MH, Decaens T, Roth G, Millet A.

Med Sci (Paris) 2022 Mar;38(3):243-245. doi: 10.1051/medsci/2022017. 

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Therapeutic siRNAs Targeting the JAK/STAT Signalling Pathway in Inflammatory Bowel Diseases

Clément F, Nougarède A, Combe S, Kermarrec F, Dey AK, Obeid P, Millet A, Navarro…

J Crohns Colitis 2022 Feb 23;16(2):286-300. doi: 10.1093/ecco-jcc/jjab129.

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A Universal Model for the Log-Normal Distribution of Elasticity in Polymeric Gels and Its Relevance to Mechanical Signature of Biological Tissues

Millet A.

Biology (Basel 2021 Jan 18;10(1):64. doi: 10.3390/biology10010064. 

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DEN-Induced Rat Model Reproduces Key Features of Human Hepatocellular Carcinoma

Kurma K, Manches O, Chuffart F, Sturm N, Gharzeddine K, Zhang J, Mercey-Ressejac M, Rousseaux…

Cancers (Basel) 2021 Oct 4;13(19):4981. doi: 10.3390/cancers13194981

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Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer

Malier M, Gharzeddine K, Laverriere MH, Marsili S, Thomas F, Decaens T, Roth G, Millet…

Cancer Res 2021 Dec 1;81(23):5963-5976. doi: 10.1158/0008-5472.CAN-21-1572.

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Measuring cell displacements in opaque tissues: dynamic light scattering in the multiple scattering regime

Brunel B, Levy V, Millet A, Dolega ME, Delon A, Pierrat R, Cappello G.

Biomed Opt Express 2020 Mar 31;11(4):2277-2297. doi: 10.1364/BOE.388360

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3D type I collagen environment leads up to a reassessment of the classification of human macrophage polarizations

Court M, Malier M, Millet A.

Biomaterials 2019 Jul;208:98-109. doi: 10.1016/j.biomaterials.2019.04.018.

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Toward Microfluidic Label-Free Isolation and Enumeration of Circulating Tumor Cells from Blood Samples

Raillon C, Che J, Thill S, Duchamp M, Desbiolles BXE, Millet A, Sollier E, Renaud…

Cytometry A. 2019 Oct;95(10):1085-1095. doi: 10.1002/cyto.a.23868

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Calreticulin Release at an Early Stage of Death Modulates the Clearance by Macrophages of Apoptotic Cells

Osman R, Tacnet-Delorme P, Kleman JP, Millet A, Frachet P.

Front Immunol 2017 Aug 23;8:1034. doi: 10.3389/fimmu.2017.01034.

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Our activities in pictures

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Our collaborations

  • Fabienne Thomas (IUCT, Toulouse, France)
  • Cédric Chauvierre (LVTS Inserm, Paris, France)
  • Felix Rico (LAI Inserm, Marseille, France)
  • Giovanni Cappelo (Liphy CNRS UGA, Grenoble, France)
  • Philippe Frachet (IBS CEA UGA, Grenoble, France)
  • Aurélie Bouchet-Spinelli (INAC CNRS-UGA-CEA, Grenoble, France)
  • Carlos Rossa Jr (Sao Paulo, Brazil)
  • Malgorzata Lekka (IFJPAN, Krakow, Poland)

Our technologies

  • Primary cell culture
  • Hypoxic culture
  • 3D cell culture
  • Transcriptomics, proteomics, metabolomics
  • Humanized in vivo models
  • RT-qPCR, Immunoblot, Flow cytometry, immunofluorescence, Immunohistology
  • Atomic Force Microscopy (AFM)