Cell cycle, autophagy, and cancer
Centre de Recherches en Cancérologie de Toulouse (CRCT)UMR1037 INSERM / Université Toulouse III Paul Sabatier / ERL5294 CNRS
2 avenue Hubert Curien
CS53717
31037 Toulouse Cedex 1- FRANCE - Toulouse
Site web - stephane.manenti@inserm.fr - 0582741635
Principal investigator
Stéphane Manenti
![](https://cfatg.org/wp-content/uploads/2023/01/photos-equipe-mars-2018.png)
Research themes
Our group, within the team directed by Dr S. Manenti at the Cancer Research Center of Toulouse, focus on autophagy in three different hematopoietic cancers: Acute Myeloid Leukeamia (AML) [2,3], Myeloproliferative Neoplasia (MPN) and ALK positive Anaplastic Large Cell Lymphoma (ALK+ ALCL) [4–6]. We are interested in several biological questions (listed below), that we address both in cell lines and in primary cells isolated from patients:
-How autophagy influences tumor cells fate (cytoprotection or cytotoxicity) under therapy? In a previous study, we demonstrated that the Bortezomib (proteasome inhibitor) induces a cytotoxic autophagy in AML cells expressing the FLT3-ITD tyrosine kinase oncogene [2]. Conversely, we observed in ALK+ ALCL cells that their treatment with Crizotinib (ALK tyrosine kinase inhibitor) induces a cytoprotective autophagy [4]. A current study, performed in myeloproliferative neoplasia (MPN) harboring the JAK2 (V617F) activating mutation, indicates that Ruxolitinib treatment (JAK1/JAK2 inhibitor) triggers also a cytoprotective autophagy. In these two last studies, combining tyrosine kinase targeted inhibition and autophagy inhibition may represent a promising therapeutic option.
-The identification of new autophagy regulators (proteins and RNAs). We recently found that the transcription factor ATF4 was required for autophagy activation in FLT3-ITD positive AML cells [3]. In Crizotinib-treated ALK+ ALCL cells, we found that the depletion of BCL-2 increases autophagy and promotes tumor cell death [6]. We are currently pursuing these works by focusing on the molecular regulations of these proteins, through translation factors and miRNAs.
-The role of autophagy in cell signaling regulation, in line with the original concept depicting the autophagosomes as new intracellular signaling platforms.
-The potential use of autophagosomes in the development of anti-cancer vaccine. We are currently investigating whether ALK+ ALCL-derived autophagosomes could be used as antigen carrier to stimulate an anti-ALK immune response.
Thus, our work aims to understand the role, the regulation, the modulation and the therapeutic use of autophagy to improve the treatment of FLT3-ITD AML, JAK2 (V617F) MPN and ALK+ ALCL. We receive funds from « La Ligue Nationale contre le Cancer », « La Fondation ARC », « Cancéropole GSO » and from the Europe Union (Horizon 2020, Marie Sklodowska-Curie Research and Innovative Programme); and we train students registered at the Toulouse Biology/Health doctoral school.
Descriptive figure
![](https://cfatg.org/wp-content/uploads/2023/01/graphical-abstract-mars-2018.png)
Publications
1. Joffre, C.; Djavaheri-Mergny, M.; Pattingre, S.; Giuriato, S. L’autophagie: le yin et le yang des cancers. Medecine/Sciences 2017, 33, 328–334, doi:10.1051/medsci/20173303021.
2. Larrue, C.; Saland, E.; Boutzen, H.; Vergez, F.; David, M.; Joffre, C.; Hospital, M. A.; Tamburini, J.; Delabesse, E.; Manenti, S.; Sarry, J. E.; Recher, C. Proteasome inhibitors induce FLT3-ITD degradation through autophagy in AML cells. Blood 2016, 127, 882–892, doi:10.1182/blood-2015-05-646497.
3. Heydt, Q.; Larrue, C.; Saland, E.; Bertoli, S.; Sarry, J.-E.; Besson, A.; Manenti, S.; Joffre, C.; Mansat-De Mas, V. Oncogenic FLT3-ITD supports autophagy via ATF4 in acute myeloid leukemia. Oncogene 2017, doi:10.1038/onc.2017.376.
4. 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, 6, 30149–30164, doi:10.18632/oncotarget.4999.
5. Frentzel, J.; Sorrentino, D.; Giuriato, S. Targeting autophagy in ALK-associated cancers. Cancers (Basel). 2017, 9 (12),161-180.
6. Torossian, A.; Frentzel, J.; Daugrois, C.; Broin, N.; Gandarillas, S.; Al Saati, T.; Lamant, L.; Brousset, P.; Giuriato, S.; Espinos, E. Blockade of crizotinib-induced BCL-2 elevation in ALK-positive ALCL triggers autophagy associated with cell death. Haematologica, in revision.
Composition de l'équipe
Charly Courdy, Etudiant M2R, charly.courdy@inserm.fr
Véronique De Mas, MCU-PH, DeMas.Veronique@iuct-oncopole.fr
Sylvie Giuriato, CR, INSERM, sylvie.giuriato@inserm.fr
Carine Joffre, CR, INSERM, carine.joffre@inserm.fr
Stéphane Manenti, DR2, CNRS, stephane.manenti@inserm.fr
Domenico Sorrentino, Etudiant en thèse, domenico.sorrentino@inserm.fr