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Studying alterations in cell homeostasis in kidney and liver diseases

from basic science:
  • metabolism
  • phosphate transporters
  • autophagy
to the translational research:
  • metabolic disorders
  • cancer
Patrice Codogno
Gérard Friedlander
Cellular homeostasis and signaling in liver and kidney pathophysiology

Patrice Codogno was trained as a biochemist and cell biologist. He received his PhD at the University Pierre and Marie Curie in Paris (France) in 1984. Patrice Codogno was hired by INSERM in 1985. In 2013 he joined INEM. He is currently research director and heads his lab since 1999. In 2013 he joined INEM to merge his team with Gérard Friedlander’s team. Patrice Codogno is internationally recognized as a leader in the field of autophagy.

Gérard Friedlander was trained as a MD at the University Paris Pierre and Marie Curie and as a PhDH (University Paris-Diderot). Gérard Friedlander is Professor of Physiology at Paris-Descartes Medical School. Since 2014 he is Dean of the Paris-Descartes Medical School. He was the Director of the Research Center “Growth and Signaling” until 2013. Gérard Friedlander is internationally recognized in the field of nephrology and phosphate transport.

Focus

  • To study the phosphate-dependent and phosphate-independent functions of phosphate transporters
  • To study the molecular aspect of autophagy and its function in stress response
  • To translate the basic knowledge into therapeutical avenues

Introduction

Phosphate (Pi) homeostasis occupies a central place in cell metabolism, proliferation, and development, and in bone mineralization. It is based on the coordinated functioning of membrane transporters (the ubiquitous PiT1 and 2, and the epithelial NPTs), of intracellular adaptor proteins, and of endocrine and paracrine modulators. Our aim is to investigate Pi homeostasis at the scale of the cell and of the whole body, in normal and pathological situations.

Autophagy is a lysosomal degradation route for cell constituents that are involved in maintaining the homeostasis of the cytoplasm. In situations of nutritional stress or other stress situations such as mechanical stress this route makes it possible to produce the nutrients required for cell metabolism or to adapt to stress by controling the cytoplasm homeostasis. Autophagy is also cytoprotective with regard to other situations involving stress. In particular, in cancer cells autophagy can be a response to both metabolic stress and to cancer treatments. At the cellular level, autophagy starts with the formation of a vacuole, the autophagosome, the formation of which depends on the presence of ATG (AuTophaGy-related) proteins. Ultimately, the autophagosome fuses with the lysosome.

Research objectives

  • Aim 1: Determine at the cellular partners of PiTs and in vivo the phenotype of conditional invaldation of PiT1 (kidney, liver, liver, adipose tissues) (Gerard Friedlander)
  • Aim 2: Carry out a molecular dissection of renal Pi loses and investigate the physiological role of Klotho (Dominique Prié)
  • Aim 3: Membrane dynamics of autophagosomal compartment (Etienne Morel)
  • Aim 4: Interplay between autophagy and the primary cilium: role in mechanical stress integration (Nicolas Dupont et Patrice Codogno)
  • Aim 5: Role of autophagy in self-renewal of cancer stem cells and their targeting in breast cancer treatment (Maryam Mehrpour)

5 main publications

  • Mai TT*, Hamaï A*, Hienzsch A* et al. - (2017) Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat Chem in press
  • Nascembeni et al. - (2017) Local detection of PtdIns3P at autophagosome biogenesis membrane platforms. Autophagy in press
  • Forand A et al. - Disruption of the phosphate tarsporter Pit1 in hepatocytes improves glucose metabolism and insulin signaling by modulating the USP7/IRS1 interaction. Cell Rep 16, 2736-48
  • Orhon I*, Dupont N* et al. - (2016) Primary cilium-dependent autophagy controls epithelial cell volume in response to fluid flow. Nat Cell Biol 18, 657-67
  • Forand et al. - (2013) Blood EKLF1-driven PiT1 expression is critical for mouse erythroid maturation in vivo and in vitro
Last 30 publications

2017

  • Gaillard F, Baron S, Timsit MO, Eladari D, Fournier C, Prot-Bertoye C, Bertocchio JP, Lamhaut L, Friedlander G, Méjean A, Legendre C, Courbebaisse M. What is the significance of ESRD risk estimation in living kidney donors? Transpl Int. 2017 Feb 2. doi: 10.1111/tri.12931. [Epub ahead of print]
  • Dupont N, Leroy C, Hamaï A, Codogno P. Long-Lived Protein Degradation During Autophagy. Methods Enzymol. 2017;588:31-40. doi: 10.1016/bs.mie.2016.09.074.
  • Dupont N, Nascimbeni AC, Morel E, Codogno P. Molecular Mechanisms of Noncanonical Autophagy. Int Rev Cell Mol Biol. 2017;328:1-23.
  • Morel E, Mehrpour M, Botti J, Dupont N, Hamaï A, Nascimbeni AC, Codogno P. Autophagy: A Druggable Process. Annu Rev Pharmacol Toxicol. 2017 Jan 6;57:375-398.
  • 2016

  • Molino D, Zemirli N, Codogno P, Morel E. The journey of the autophagosome through mammalian cell organelles and membranes. J Mol Biol. 2016 Dec 13. [Epub ahead of print]
  • Nascimbeni AC, Codogno P, Morel E. Phosphatidylinositol-3-phosphate in the regulation of autophagy membrane dynamics. FEBS J. 2016 Dec 14. doi: 10.1111/febs.13987. [Epub ahead of print]
  • Bienaimé F, Muorah M, Yammine L, Burtin M, Nguyen C, Baron W, Garbay S, Viau A, Broueilh M, Blanc T, Peters D, Poli V, Anglicheau D, Friedlander G, Pontoglio M, Gallazzini M, Terzi F. Stat3 Controls Tubulointerstitial Communication during CKD. J Am Soc Nephrol. 2016 Dec;27(12):3690-3705.
  • Bernichtein S, Pigat N, Barry Delongchamps N, Boutillon F, Verkarre V, Camparo P, Reyes-Gomez E, Méjean A, Oudard SM, Lepicard EM, Viltard M, Souberbielle JC, Friedlander G, Capiod T, Goffin V. Vitamin D3 prevents calcium-induced progression of early-stage prostate tumors by counteracting TRPC6 and calcium sensing receptor upregulation. Cancer Res. 2016 Nov 22. pii: canres.0687.2016. [Epub ahead of print]
  • Courbebaisse M, Mehel H, Petit-Hoang C, Ribeil JA, Sabbah L, Tuloup-Minguez V, Bergerat D, Arlet JB, Stanislas A, Souberbielle JC, Le Clésiau H, Fischmeister R, Friedlander G, Prié D. Carboxy-terminal fragment of fibroblast growth factor 23 induces heart hypertrophy in sickle cell disease. Haematologica. 2016 Oct 27. pii: haematol.2016.150987. [Epub ahead of print] No abstract available.
  • Capiod T, Bernichtein S, Pigat N, Boutillon F, Barry Delongchamps N, Souberbielle J, Friedlander G, Goffin V. Effets opposés du calcium et de la vitamine D dans le développement du cancer de la prostate. Prog Urol. 2016 Nov;26(13):777. doi: 10.1016/j.purol.2016.07.218. French. No abstract available.
  • Forand A, Koumakis E, Rousseau A, Sassier Y, Journe C, Merlin JF, Leroy C, Boitez V, Codogno P, Friedlander G, Cohen I. Disruption of the Phosphate Transporter Pit1 in Hepatocytes Improves Glucose Metabolism and Insulin Signaling by Modulating the USP7/IRS1 Interaction. Cell Rep. 2016 Sep 6;16(10):2736-48. doi: 10.1016/j.celrep.2016.08.012.
  • Duroux-Richard I, Roubert C, Ammari M, Présumey J, Grün JR, Häupl T, Grützkau A, Lecellier CH, Boitez V, Codogno P, Escoubet J, Pers YM, Jorgensen C, Apparailly F. miR-125b controls monocyte adaptation to inflammation through mitochondrial metabolism and dynamics. Blood. 2016 Oct 4. pii: blood-2016-02-697003. [Epub ahead of print]
  • Dupont N, Codogno P. Autophagy transduces physical constraints into biological responses. Int J Biochem Cell Biol. 2016 Oct;79:419-426. doi: 10.1016/j.biocel.2016.08.021.
  • Orhon I, Dupont N, Codogno P. Primary cilium and autophagy: the Avengers of cell-size regulation. Autophagy. 2016 Aug 2:0. [Epub ahead of print]
  • Botti-Millet J, Nascimbeni AC, Dupont N, Morel E, Codogno P. Fine-tuning autophagy: from transcriptional to post-translational regulation. Am J Physiol Cell Physiol. 2016 Sep 1;311(3):C351-62.
  • Courbebaisse M, Gaillard F, Tissier AM, Fournier C, Le Nestour A, Corréas JM, Slimani-Thevenet H, Martinez F, Léon C, Eladari D, Timsit MO, Otal P, Hignette C, Friedlander G, Méjean A, Houillier P, Kamar N, Legendre C. Association of mGFR of the Remaining Kidney Divided by Its Volume before Donation with Functional Gain in mGFR among Living Kidney Donors. Clin J Am Soc Nephrol. 2016 Aug 8;11(8):1369-76.
  • Bettoun A, Joffre C, Zago G, Surdez D, Vallerand D, Gundogdu R, Sharif AA, Gomez M, Cascone I, Meunier B, White MA, Codogno P, Parrini MC, Camonis JH, Hergovich A. Mitochondrial clearance by the STK38 kinase supports oncogenic Ras-induced cell transformation. Oncotarget. 2016 Jul 12;7(28):44142-44160.
  • Orhon I, Dupont N, Zaidan M, Boitez V, Burtin M, Schmitt A, Capiod T, Viau A, Beau I, Wolfgang Kuehn E, Friedlander G, Terzi F, Codogno P. Primary-cilium-dependent autophagy controls epithelial cell volume in response to fluid flow. Nat Cell Biol. 2016 Jun;18(6):657-67.
  • Gaillard F, Flamant M, Lemoine S, Baron S, Timsit MO, Eladari D, Fournier C, Prot-Bertoye C, Bertocchio JP, Vidal-Petiot E, Lamhaut L, Morelon E, Péraldi MN, Vrtovsnik F, Friedlander G, Méjean A, Houillier P, Legendre C, Courbebaisse M. Estimated or Measured GFR in Living Kidney Donors Work-up? Am J Transplant. 2016 Jun 6. doi: 10.1111/ajt.13908. [Epub ahead of print]
  • Codogno P, Klionsky DJ. Opening new doors in autophagy research: Patrice Codogno Autophagy. 2016 Jun 2;12(6):1063-8. doi: 10.1080/15548627.2016.1170267. Epub 2016 May 9. PMID: 27158743.
  • Gaillard F, Pavlov P, Tissier AM, Harache B, Eladari D, Timsit MO, Fournier C, Léon C, Hignette C, Friedlander G, Correas JM, Weinmann P, Méjean A, Houillier P, Legendre C, Courbebaisse M. Use of computed tomography assessed kidney length to predict split renal GFR in living kidney donors. Eur Radiol. 2016 May 24. [Epub ahead of print]
  • Casas C, Codogno P, Pinti M, Batoko H, Morán M, Proikas-Cezanne T, Reggiori F, Sirko A, Soengas MS, Velasco G, Lafont F, Lane J, Faure M, Cossarizza A. TRANSAUTOPHAGY: European network for multidisciplinary research and translation of autophagy knowledge. Autophagy. 2016;12(3):614-7.
  • Joffre C, Codogno P, Fanto M, Hergovich A, Camonis J. STK38 at the crossroad between autophagy and apoptosis. Autophagy. 2016 Feb 18:0. [Epub ahead of print] No abstract available.
  • Rolando M, Escoll P, Nora T, Botti J, Boitez V, Bedia C, Daniels C, Abraham G, Stogios PJ, Skarina T, Christophe C, Dervins-Ravault D, Cazalet C, Hilbi H, Rupasinghe TW, Tull D, McConville MJ, Ong SY, Hartland EL, Codogno P, Levade T, Naderer T, Savchenko A, Buchrieser C. Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy. Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):1901-6.
  • Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, and al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016 Jan 2;12(1):1-222. No abstract available.
  • Delevoye C, Heiligenstein X, Ripoll L, Gilles-Marsens F, Dennis MK, Linares RA, Derman L, Gokhale A, Morel E, Faundez V, Marks MS, Raposo G. BLOC-1 Brings Together the Actin and Microtubule Cytoskeletons to Generate Recycling Endosomes. Curr Biol. 2016 Jan 11;26(1):1-13.
  • El Karoui K, Viau A, Dellis O, Bagattin A, Nguyen C, Baron W, Burtin M, Broueilh M, Heidet L, Mollet G, Druilhe A, Antignac C, Knebelmann B, Friedlander G, Bienaimé F, Gallazzini M, Terzi F. Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2. Nat Commun. 2016 Jan 20;7:10330. doi: 10.1038/ncomms10330.
  • 2015

  • Pujals A, Favre L, Pioche-Durieu C, Robert A, Meurice G, Le Gentil M, Chelouah S, Martin-Garcia N, Le Cam E, Guettier C, Raphaël M, Vassilev LT, Gaulard P, Codogno P, Lipinski M, Wiels J. Constitutive autophagy contributes to resistance to TP53-mediated apoptosis in Epstein-Barr virus-positive latency III B-cell lymphoproliferations. Autophagy. 2015 Nov;11(12):2275-87.
  • Joffre C, Dupont N, Hoa L, Gomez V, Pardo R, Gonçalves-Pimentel C, Achard P, Bettoun A, Meunier B, Bauvy C, Cascone I, Codogno P, Fanto M, Hergovich A, Camonis J. The Pro-apoptotic STK38 Kinase Is a New Beclin1 Partner Positively Regulating Autophagy. Curr Biol. 2015 Sep 16. pii: S0960-9822(15)01002-7. doi: 10.1016/j.cub.2015.08.031. [Epub ahead of print]
  • Mitou G, Frentzel J, Desquesnes A, Le Gonidec S, AlSaati T, Beau I, Lamant L, Meggetto F, Espinos E, Codogno P, Brousset P, Giuriato S. Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma. Oncotarget. 2015 Oct 6;6(30):30149-64.
  • Cursio R, Colosetti P, Codogno P, Cuervo AM, Shen HM. The role of autophagy in liver diseases: mechanisms and potential therapeutic targets. Biomed Res Int. 2015;2015:480508. doi: 10.1155/2015/480508. Epub 2015 Mar 19. PubMed PMID: 25866785; PubMed Central PMCID: PMC4383141.
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