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Integrins in Immune Cells

Frédéric Lagarrigue

Group Leader

Our research team has been launched in January 2021 within the framework of the ATIP-AVENIR program in partnership with the Fondation ARC for cancer research. We investigate the regulation of integrin function in immune cells with a potential for therapeutic intervention in cancer and inflammatory diseases.  

Integrins are a widely expressed family of cell adhesion receptors that participate in cell interactions in many tissues. Their role in immune cells is essential for leukocyte trafficking, activation and function to shape a successful immunity. Hence integrins are attractive targets for recalibrating immune responses within local microenvironments. They are proven therapeutic targets in many diseases but direct targeting of their extracellular domain to interfere with their function often leads to adverse effects limiting the use of integrin antagonists. Instead, we intend to target intracellular signaling events that orchestrate integrin activities in immune cells.

 

In this regard we study the diversity and specificity of these signaling pathways in various cellular contexts and investigate their potential to selectively manipulate specific immune cell subsets for therapeutic purposes. This underestimated strategy aligns with the emerging paradigm that signaling events in hematopoietic cells operate in both a cell-type and integrin-specific manner.

 

We focus primarily on the integrin-dependent infiltration of macrophages within the vast majority of solid tumors. Poor prognosis largely correlates with the abundancy of tumor-associated-macrophages as they enhance disease progression. We endeavor to devise novel strategies for blockade of macrophage infiltration in tumors to synergize with combination therapies that simultaneously neutralize both protumor stromal cells and cancer cells. Additionally, macrophage tissue infiltration occurs in many other pathological contexts including inflammation and infectious diseases; hence our research could have far-reaching implications beyond cancer.


Our major strength is the use of elegant genetically modified mice bearing knock-out or knock-in mutations of key integrin signaling regulators, which constitute a unique asset to the successful completion of our research objectives. To this end, we use an interdisciplinary approach, combining immune cell biology, molecular biology, biophysics, proteomics, advanced techniques in microscopy, and complementary in vivo and ex vivo approaches. 
 

 

Scanning electron micrograph showing the adhesion of a macrophage onto the peritoneal basement membrane.

© Renaud Poincloux

 

Main Publication

 

  • Sun H, Lagarrigue F, Wang H et al. (2021) Distinct integrin activation pathways for effector and regulatory T cell trafficking and function. J Exp Med 218:e20201524. 
  • Lagarrigue F*, Paul DS*, Gingras AR* et al. (2020) Talin-1 is the principal platelet Rap1 effector of integrin activation. Blood 136:1180-1190. 
  • Gingras AR*, Lagarrigue F*, Cuevas MN et al. (2019) Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem. J Cell Biol 218:1799-1809. 
     
  • Lagarrigue F, Gingras AR, Paul DS et al. (2018) Rap1 binding to the talin1 F0 domain makes a minimal contribution to murine platelet GPIIb-IIIa activation. Blood Adv 2:2358-2368. 
  • Lagarrigue F, Gertler FB, Ginsberg MH et al.  Cantor JM. Cutting Edge: Loss of T Cell RIAM Precludes Conjugate Formation with APC and Prevents Immune-Mediated Diabetes. J Immunol 198:3410-3415.
  • Lagarrigue F*, Vikas Anekal P*, Lee HS et al. (2015) A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration. Nat Commun 6:8492. 
     

 

 

  • Sun H, Lagarrigue F, Wang H et al. (2021) Distinct integrin activation pathways for effector and regulatory T cell trafficking and function. J Exp Med 218:e20201524. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/33104169/
  •  Ablack JN, Ortiz J, Bajaj J et al. (2020) MARCH Proteins Mediate Responses to Antitumor Antibodies. J Immunol 205:2883-2892. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/33077644/
  • Lagarrigue F*, Paul DS*, Gingras AR* et al. (2020) Talin-1 is the principal platelet Rap1 effector of integrin activation. Blood 136:1180-1190. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/32518959/
  • Gingras AR*, Lagarrigue F*, Cuevas MN et al. (2019) Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem. J Cell Biol 218:1799-1809. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/30988001/
  • Lopez-Ramirez MA, Pham A, Girard R et al. (2018) Cerebral cavernous malformations form an anticoagulant vascular domain. Blood 133:193-204 https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/30442679/
  • Lagarrigue F, Gingras AR, Paul DS et al. (2018) Rap1 binding to the talin1 F0 domain makes a minimal contribution to murine platelet GPIIb-IIIa activation. Blood Adv 2:2358-2368. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/30242097/
  • Sun H, Lagarrigue F, Gingras AR et al. (2018) Transmission of integrin β7 transmembrane domain topology enables gut lymphoid tissue development. J Cell Biol 217:1453-1465. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/29535192/
  • Lopez-Ramirez MA, Fonseca G, Zeineddine HA et al. (2017) Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations. J Exp Med 214:3331-3346. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/28970240/
  • Lagarrigue F, Gertler FB, Ginsberg MH et al. (2017) Cutting Edge: Loss of T Cell RIAM Precludes Conjugate Formation with APC and Prevents Immune-Mediated Diabetes. J Immunol 198:3410-3415. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/28348273/
  • Lagarrigue F, Kim C, Ginsberg MH. (2016) The Rap1-RIAM-talin axis of integrin activation and blood cell function. Blood 128:479-87. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/27207789/
     
  • Lagarrigue F*, Vikas Anekal P*, Lee HS et al. (2015) A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration. Nat Commun 6:8492. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/26419705/
  • Viaud J, Lagarrigue F, Ramel D et al. (2014) Phosphatidylinositol 5-phosphate regulates invasion through binding and activation of Tiam1. Nat Commun 5:4080. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/24905281/
  • Ye F*, Lagarrigue F*, Ginsberg MH. (2014) SnapShot: talin and the modular nature of the integrin adhesome. Cell 156:1340-1340.e1. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/24630731/
  •  Dejean E, Foisseau M, Lagarrigue F et al. (2012) ALK+ALCLs induce cutaneous, HMGB-1-dependent IL-8/CXCL8 production by keratinocytes through NF-κB activation. Blood 119:4698-707. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/22394598/
  • Ramel D, Lagarrigue F, Pons V et al. (2011) Shigella flexneri infection generates the lipid PI5P to alter endocytosis and prevent termination of EGFR signaling. Sci Signal 4:ra61. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/21934107/
  • Dupuis-Coronas S, Lagarrigue F, Ramel D et al. (2011) The nucleophosmin-anaplastic lymphoma kinase oncogene interacts, activates, and uses the kinase PIKfyve to increase invasiveness. J Biol Chem 286:32105-14. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/21737449/
  • Lagarrigue F, Dupuis-Coronas S, Ramel D et al. (2010) Matrix metalloproteinase-9 is upregulated in nucleophosmin-anaplastic lymphoma kinase-positive anaplastic lymphomas and activated at the cell surface by the chaperone heat shock protein 90 to promote cell invasion. Cancer Res 70:6978-87. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/20699364/
  • Ramel D, Lagarrigue F, Dupuis-Coronas S et al. (2009) PtdIns5P protects Akt from dephosphorylation through PP2A inhibition. Biochem Biophys Res Commun 387:127-31. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/19576174/
  • Coronas S, Lagarrigue F, Ramel D et al. (2008) Elevated levels of PtdIns5P in NPM-ALK transformed cells: implication of PIKfyve. Biochem Biophys Res Commun 372:351-5. https://pubmed-ncbi-nlm-nih-gov.insb.bib.cnrs.fr/18501703/

 

Collaborations

  • Christel Verollet & Renaud Poincloux, IPBS Toulouse, France
  • Mark Ginsberg, University of California San Diego, USA
  • Nicolas Bidère, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, France
  • Christine Jean, Centre de Recherches en Cancérologie de Toulouse, France
  • Claudine Blin, Laboratoire de Physio-Médecine Moléculaire Nice, France
  • Odile Schiltz, IPBS Toulouse, France
  • CRISPRit, Institut Curie, France
     

Funding

Our group received several grants and fellowships from local, national and European agencies and charities:

  • ATIP-Avenir 2020, young team leader program
  • Fondation ARC pour la Recherche sur le Cancer
  • Marie Sklodowska-Curie Individual Fellowship
  • Fondation Toulouse Cancer Santé
  • Fondation de France
  • La Ligue Nationale Contre le Cancer