Function of ERM proteins in the migration of tumor-associated macrophages.

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    Biological sciencesBiology
    First Stage Researcher (R1)
    Recognised Researcher (R2)
    Established Researcher (R3)
    Leading Researcher (R4)
    09/11/2019 00:00 - Europe/Athens
    France › Toulouse

Macrophages are innate immune cells that are present in all body tissues to maintain tissue homeostasis and immune surveillance. They display a huge plasticity to adapt to the various environments they encounter, mainly by reorganizing their cortical cytoskeleton to dynamically adapt their shape. In several pathological conditions (infection, injury, cancer, inflammation), macrophages derived from blood monocytes are recruited into tissues and either participate to disease resolution and tissue repair or help with disease progression as described in chronic inflammatory diseases and cancer. A therapeutic strategy to limit tissue infiltration of pathogenic macrophages is to target their migration. Over the last 10 years, the team of Isabelle Maridonneau-Parini at Toulouse University has made an important breakthrough at deciphering the migration mechanisms in 3D environments of human macrophages derived from blood monocytes. We revealed that macrophages use two migration modes and that the structure of the extracellular matrix (ECM) dictates the migration mode that is used:  the amoeboid mode in porous environments and the mesenchymal mode in dense environments, which is dependent on proteases and F-actin cell structures called podosomes. Intravital microscopy further revealed that tumor-associated macrophages (TAM) use the mesenchymal migration in a mouse model of fibrosarcoma while macrophages at the tumor periphery or in inflamed derma use the amoeboid mode. In human breast tumor explants, macrophages also use the mesenchymal mode. We could decrease the number of TAMs by treating mice with inhibitors of matrix metalloproteases and consequently, tumor growth was diminished. Our objective is to identify new effectors of macrophage tissue infiltration, with the ultimate goal to identify potential therapeutic targets to limit deleterious tissue infiltration of macrophages and in particular TAMs.

One family of proteins that can promote macrophage infiltration are ERM proteins. This family is composed of 3 paralogs, Ezrin, Radixin and Moesin. The laboratory of Sébastien Carréno at University of Montréal has contributed to show that ERMs are dynamic linkers between actin filaments, microtubules and the cell cortex. ERMs control cell shape by integrating acto-myosin contractions at the plasma membrane and stabilizing microtubule ends. In a pathological context, Ezrin, Radixin or Moesin were shown to be overactivated during cancer progression, including in metastatic rhabdomyosarcoma, osteosarcoma, prostate cancer and mammary carcinoma. How ERMs promote metastasis of cancer cells is still not perfectly understood. However, the current model is that ERMs control the rapid cortical changes necessary for cells to migrate and invade efficiently. In addition, Ezrin was shown to regulate the dynamics of invadopodia, a podosome-related structure, during breast cancer cell invasion. Besides their role during mesenchymal migration, Ezrin and Moesin have also been shown to promote amoeboid invasion of melanoma cells. Thus, understanding how these proteins promote cell invasion is important for both fundamental and biomedical research. Recently, two small molecules that inhibit ERM function were identified. Both molecules (MMV667492 and NSC305787) showed potent effect against invasion and metastasis of osteosarcoma and breast cancer cells. Interestingly, NSC668394 was recently shown to affect migration of neutrophils. Yet the involvement of ERMs for macrophage mesenchymal migration and tumor infiltration has been overlooked.

The function of ERMs during macrophage infiltration will be studied both in vitro and in vivo taking advantage of the knowledge and know-how that both labs have developed. The lab of Isabelle Maridonneau-Parini has developed in vitro, ex vivo and in vivo assays of macrophage migration, it is also expert in podosome biology; The lab of Sébastien Carréno has developed several cell biology and biochemical approaches to study ERM functions during cell invasion: Study of real-time invasion using electrical-impedance, probing ERM activation in situ using BRET and FRET biosensors, assaying ERM function using validated shRNA and CRISPR sgRNA as well as novel proprietary ERM small molecule inhibitor, testing specific ERM function using a battery of several mutant cDNA.

Funding category: Contrat doctoral

PHD Country: France

Offer Requirements

Specific Requirements

We are seeking for a self-motivated and collaborative individual to join our groups as a PhD student in cotutelle. The ideal candidate will have a cell biology and cell signaling background. He/She will receive a multidisciplinary training in molecular biology, biochemical and cell biology approaches and mouse models. The PhD student will undertake this project for the first 18 months in Toulouse and the last 18 months in Montreal. Some back-and-forth visits in both laboratories may be necessary.

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EURAXESS offer ID: 445019
Posting organisation offer ID: 87369


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