Autophagy, membrane dynamics, stress, and cancer

Research themes

Our group has a long standing experience in the study of the macroautophagy (hereafter referred to as autophagy) signaling in cancer cells. We have reported the role of phosphatidylinositol 3-kinases, sphingolipids, and GTPases in the regulation of autophagy. More recently, we described a novel non-canonical form of autophagy that is independent of Beclin 1 and Vsp34. Our project follows three axes described below.

• Membrane dynamics of autophagosomal compartment (Anna Nascimbeni, Etienne Morel)

Our goal is to better understand the molecular events that regulate the biogenesis of autophagosomes in mammals, notably during early steps of autophagy, such as emergence of omegasomes and phagophores. We are currently focusing on 1) endoplasmic reticulum (ER) local modifications that include phosphatidylinositol-3-phosphate (PI3P) synthesis, recruitment of specific proteins such as WIPIs, DFCP1/ZFYVE1, and VMP1; 2) on dynamics of ER-plasma membrane contact sites; and 3) on local recruitment of scaffolding proteins and cytoskeleton regulators that could – directly or indirectly – participate in the control of the membrane curvature and deformation necessary for phagophore biogenesis. Finally, we investigate the putative crosstalk between autophagosomes and early endosomes in terms of endosomal functions and signaling and in terms of membrane dynamics contributions (e.g., autophagy regulation, amphisome biogenesis, and autophagosome trafficking).

• Interplay between autophagy and the primary cilium: role in mechanical stress integration (Idil Orhon, Nicolas Dupont)

This research is the follow up on the work that demonstrated the molecular and functional cross-talk between autophagy and the primary cilium (proteins engaged in the ciliogenesis and signaling emanating from the primary cilium). We are currently focused on elucidation of the mechanism of the regulation of autophagy in kidney epithelial cells upon mechanical stress such as shear stress induced by fluid flow. We are characterizing the cellular signaling pathways involved in this autophagy regulation (e.g., mTOR, AMPK, calcium) and the molecular dialog between autophagy-related (ATG) proteins and proteins involved in ciliogenesis. Finally, we have begun to study the role of renal primary cilium-dependent autophagy in the control of the cell volume and that of the planar cell polarity in physiology and pathophysiological situations by using in vitro and mouse models.

• Role of autophagy in self-renewal of cancer stem cells and their targeting in breast cancer treatment (Ahmed Hamaï, Joelle Botti, Maryam Mehrpour)

Breast cancer tissue contains a small population of cells known as cancer stem-like cells (CSCs) that have the ability to self-renew. CSCs are responsible for tumor recurrence and metastasis and for tumor resistance to anticancer therapies. We have recently shown that autophagy is essential for the maintenance and the tumorigenicity of these CSCs, which have a more robust autophagic activity than the non-CSC population. Recently, we showed that targeting autophagy by salinomycin (Sal) sensitives CSCs to cell death. For this project, we will address the role of autophagy in the maintenance, self-renewal, and plasticity of CSCs (from cancer and normal tissue) through its roles in i) cellular integrity (such as mitophagy, aggrephagy), which is essential for the cellular longevity and ii) metabolic reprogramming, which characterizes the CSC status. As a therapeutic approach, we plan to synthesis a family of chemical compounds (Sal analogues) targeting CSCs. We will focus on the molecular mechanism of action of the lead compound. This project will provide a better understanding of the role of autophagy in carcinogenesis, particularly in breast CSCs (BCSCs). In the short term, we will consider therapeutic clinical trials with the lead compound. In the long term, our work could result in the development of approaches for targeting autophagy in tumor cells to circumvent resistance that develops in BCSCs, which is a major limitation to cancer therapy. Part of this project is subject to maturation work in collaboration with SATT IDFINNOV (structure d’ acceleration de transfert de technologies d’Ile de France innovation) in order to provide proof of concept on therapeutic potential of lead analogue. (Invention disclosure: M. Mehrpour et al.).

Publications

– Levine B, Packer M, Codogno P. (2015) Development of autophagy inducers in clinical medicine.
J Clin Invest 125: 14-24
– Orhon I, Dupont N, Pampliega O, Cuervo AM, Codogno P. (2014) Autophagy and regulation of cilia function and assembly.
Cell Death Differ. Online Oct 31.
– Dupont N, Chauhan S, Arko-Mensah J, Castillo EF, Masedunskas A, Weigert R, Robenek H, Proikas-Cezanne T, Deretic V. (2014) Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis.
Curr Biol 24: 609-20.
– Khaldoun SA, Emond-Boisjoly MA, Chateau D, Carrière V, Lacasa M, Rousset M, Demignot S, Morel E. (2014) Autophagosomes contribute to intracellular lipid distribution in enterocytes.
Mol Biol Cell 25: 118-32.
– Yue W, Hamaï A, Tonelli G, Bauvy C, Nicolas V, Tharinger H, Codogno P, Mehrpour M. (2013)
Inhibition of the autophagic flux by salinomycin in breast cancer stem-like/progenitor cells interferes with their maintenance.
Autophagy 9: 714-29.
– Morel E, Chamoun Z, Lasiecka ZM, Chan RB, Williamson RL, Vetanovetz C, Dall’Armi C, Simoes S, Point Du Jour KS, McCabe BD, Small SA, Di Paolo G. (2013) Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system.
Nat Commun 4: 2250.
– Boya P, Reggiori F, Codogno P. (2013) Emerging regulation and functions of autophagy.
Nat Cell Biol 15:713-20.
– Tuloup-Minguez V, Hamaï A, Greffard A, Nicolas V, Codogno P, Botti J. (2013)
Autophagy modulates cell migration and β1 integrin membrane recycling.
Cell Cycle 12:3317-28.
– Pampliega O, Orhon I, Patel B, Sridhar S, Díaz-Carretero A, Beau I, Codogno P, Satir BH, Satir P, Cuervo AM. (2013) Functional interaction between autophagy and ciliogenesis.
Nature 502:194-200.
– Gong C, Bauvy C, Tonelli G, Yue W, Deloménie C, Nicolas V, Zhu Y, Domergue V, Marin-Esteban V, Tharinger H, Delbos L, Gary-Gouy H, Morel AP, Ghavami S, Song E, Codogno P, Mehrpour M. (2013)
Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells.
Oncogene 32: 2261-72,
– Nascimbeni AC, Fanin M, Masiero E, Angelini C, Sandri M. (2012) The role of autophagy in the pathogenesis of glycogen storage disease type II (GSDII).
Cell Death Differ 19: 1698-708.
– Tuloup-Minguez V, Greffard A, Codogno P, Botti J.
Regulation of autophagy by extracellular matrix glycoproteins in HeLa cells.
Autophagy 2011 7:27-39.
– Codogno P, Mehrpour M, Proikas-Cezanne T. (2011) Canonical and non-canonical autophagy: variations on a common theme of self-eating?
Nat Rev Mol Cell Biol. 2011 13: 7-12.

Composition de l'équipe

Patrice Codogno (DRCE INSERM)
Maryam Mehrpour (CR1 INSERM)
Etienne Morel (CR1 INSERM)
Joëlle Botti (MCF Université Paris-Diderot)
Nicolas Dupont (post-doctorant)
Ahmed Hamaï (post-doctorant)
Anna Nascimbeni (post-doctorante)
Idil Orhon (post-doctorante)