Où docteurs et entreprises se rencontrent
Menu
Connexion

Vous avez déjà un compte ?

Nouvel utilisateur ?

Mot de passe oublié

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

ABG-87369 Sujet de Thèse
11/09/2019 > 25 et < 35 K€ brut annuel
CNRS IPBS
Toulouse - Occitanie - France
Function of ERM proteins in the migration of tumor-associated macrophages.
  • Biologie

Description du sujet

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.

Nature du financement

Contrat doctoral

Précisions sur le financement

Présentation établissement et labo d'accueil

CNRS IPBS

IPBS, Université de Toulouse, CNRS, UPS, France

 

&

 

IRIC, Université de Montréal, Département de Pathologie et Biologie Cellulaire

 

 

Selected references :

Team 1 :

  • Souriant S, Balboa L, Pingris K, Kviatcovsky D, Cougoule C, Lastrucci C, Bah A, Gasser R, Poincloux R, Raynaud-Messina B, Al Saati T, Inwentarz S, Poggi S, Moraña EJ, Gonzalez-Montaner P, Corti M, Lagane B, Vergne I, Allers C, Kaushal D, Kuroda MJ, Sasiain MDC, Neyrolles O*, Maridonneau-Parini I*, Lugo-Villarino G*, Vérollet C*.  2019 “Tuberculosis boosts HIV-1 production by macrophages through IL-10/STAT3-dependent tunneling nanotube formation". Cell Rep, 2019 in press IF:8.0
  • Raynaud-Messina B, Bracq L, Dupont M, Souriant S, Usmani SM, Proag A, Pingris K, Soldan V, Thibault C, Capilla F, Al Saati T, Gennero I, Jurdic P, Jolicoeur P, Davignon JL, Mempel TR, Benichou S, Maridonneau-Parini I*, Verollet C*. 2018 The bone degradation machinery of osteoclasts: a novel HIV-1 target that contributes to bone loss. Proc Natl Acad Sci USA 115(11):E2556-E2565 IF:9.5
  • Gui P, Ben-Neji M, Belozertseva E, Dalenc F, Franchet C, Gilhodes J, Labrousse A, Bellard E, Golzio M, Poincloux  R, Maridonneau-Parini I*, Le Cabec V*. 2018 The protease-dependent mesenchymal migration of tumor-associated macrophages is a novel target in cancer immunotherapy. Cancer Immunol Res (2018) 6(11):1337-1351 IF:9.2
  • Desvignes E, Bouissou A, Laborde A, Mangeat T, Proag A, Vieu C, Thibault C, Maridonneau-Parini I*, Poincloux R*. 2018 Nanoscale forces during confined cell migration. Nano Lett 10;18(10):6326-6333 IF:12.1
  • Bouissou A#, Proag A#, Bourg N, Pingris K, Cabriel C, Balor S, Mangeat T, Thibault C, Vieu C, Dupuis G, Fort E, Lévêque-Fort S, Maridonneau-Parini I*, Poincloux R*.  2017 Podosome Force Generation Machinery: a Local Balance between Protrusion at the Core and Traction at the Ring. ACS Nano 11(4):4028-4040 IF:13.7
  • Verollet C, Souriant S, Bonnaud E, Jolicoeur P, Raynaud-Messina B, Kinnaer C, Fourquaux I, Imle A, Benichou S, Fackler O, Poincloux R, Maridonneau-Parini I. 2015 HIV-1 reprograms the migration of macrophages. Blood 125(10):1611-22 IF:15.1
  • Proag A#, Bouissou A#, Mangeat T, Voituriez R, Delobelle P, Thibault C, Vieu C, Maridonneau-Parini I*, Poincloux R*.  2015 Working together: Spatial synchrony in the force and actin dynamics of podosome first neighbors. ACS Nano 9(4):3800-13 IF:13.7
  • Lastrucci C, Bénard A, Balboa L, Pingris K, Souriant S, Poincloux R, Al Saati T, Rasolofo V, González-Montaner P, Inwentarz S, Moraña E, Kondova I, Verreck FAW, Sasiain MC, Neyrolles O*, Maridonneau-Parini I*, Lugo-Villarino G and Cougoule C. 2015 Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis. Cell Res 25(12):1333-51 IF:15.4
  • Labernadie A, Bouissou A, Delobelle P, Balor S, Voituriez R, Proag A, Fourquaux I, Thibault C, Vieu C, Poincloux R*, Charrière GM*, Maridonneau-Parini I*. 2014 Protrusion Force Microscopy reveals oscillatory force generation and mechanosensing activity of human macrophage podosomes. Nat Commun 5:5343 IF:12.4

Team 2:

  • Misshapen coordinates protrusion restriction and actomyosin contractility during collective cell migration. Plutoni C, Keil S, Zeledon C, Alberici Delsin LE, Decelle B, Carreno S, Roux PP, Emery G. Nature Com. In press.
  • PTEN reduces endosomal PtdIns(4,5)P2 in a phosphatase independent manner via a PLC pathway. Mondin V, Ben El Kadhi K, Cauvin C, Jackson-Crawford A, Bélanger E, Decelle B, Salomon R, Lowe M, Echard A, Carreno S. J. Cell Biol. 2019 Jul 1;218(7):2198-2214.
  • IPIP27 Coordinates PtdIns(4,5)P2 Homeostasis for Successful Cytokinesis.  Carim SC, Ben El Kadhi K, Yan G, Sweeney ST, Hickson GR, Carréno S*, Lowe M*.  Curr. Biol. 2019;29(5):775-789.e7. *Corresponding authors
  • Proteomics Screen Identifies Class I Rab11 Family Interacting Proteins as Key Regulators of Cytokinesis. Laflamme C, Galan JA, Ben El Kadhi K, Méant A, Zeledon C, Carréno S, Roux PP, Emery G. Mol. Cell. Biol. 2017;37(3).
  • Interdomain allosteric regulation of Polo kinase by Aurora B and Map205 is required for cytokinesis. Kachaner D, Pinson X, Ben El Kadhi KB, Normandin K, Talje L, Lavoie H, Lépine G, Carréno S, Kwok BH, Hickson GR, Archambault V.  J. Cell Biol. 2014;207(2):201-11.
  • DHTP is an allosteric inhibitor of the kinesin-13 family of microtubule depolymerases. Talje L, Ben El Kadhi K, Atchia K, Tremblay-Boudreault T, Carreno S, Kwok BH. FEBS Lett. 2014;588(14):2315-20.
  • The actin-binding ERM protein Moesin binds to and stabilizes microtubules at the cell cortex. Solinet S, Mahmud K, Stewman SF, Ben El Kadhi K, Decelle B, Talje L, Ma A, Kwok BH, Carreno S. J. Cell Biol. 2013;202(2):251-60.
  • Gab2 Phosphorylation by RSK Inhibits Shp2 Recruitment and Cell Motility. Zhang X, Lavoie G, Fort L, Huttlin EL, Tcherkezian J, Galan JA, Gu H, Gygi SP, Carreno S, Roux PP. Mol. Cell. Biol. 2013;33(8):1657-70.
  • Molecular networks linked by Moesin drive remodeling of the cell cortex during mitosis. Roubinet C, Decelle B, Chicanne G, Dorn JF, Payrastre B, Payre F, Carreno S. J. Cell Biol. 2011;195(1):99-112.
  • The inositol 5-phosphatase dOCRL controls PI(4,5)P2 homeostasis and is necessary for cytokinesis. Ben El Kadhi K, Roubinet C, Solinet S, Emery G, Carréno S. Curr. Biol. 2011;21(12):1074-9.

Profil du candidat

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.

Date limite de candidature

Partager via
Postuler
Fermer

Vous avez déjà un compte ?

Nouvel utilisateur ?


Mot de passe oublié
Besoin d'informations ?

Vous souhaitez recevoir une ou plusieurs lettres d’information de l’ABG. Chaque mois des actualités, des offres, des outils, un agenda…

item1 item1 item1 item1
item1 item1
Ils nous font confiance