The team aims at understanding and targeting the cellular processes associated with the control of protein homeostasis (proteostasis) in cancer cells. In particular we focus on the control of proteostasis in the first compartment of the secretory pathway, the Endoplasmic Reticulum (ER). In transformed and cancer cells, the ER homeostasis is often perturbed as protein folding demand exceeds cell’s folding capacity. This leads to a situation called ER stress and activation of the adaptive Unfolded Protein Response (UPR). The UPR is mediated by three protein sensors named PERK, ATF6 and IRE1 (Figure 1) that transduce signals aiming at restoring ER homeostasis. The activation of the stress sensors has been shown to provide selective advantages to tumor cells through enhancing their adaptive properties either towards intrinsic stresses such as oncogene expression or extrinsic stresses such as nutrient deprivation or chemotherapeutic attacks. As a consequence these pathways constitute attractive therapeutic targets whose modulation will alter cancer cells plasticity and adaptive properties.
IRE1 signaling in cancers
For the past 15 years we have been investigating the role of IRE1 in glioma, the most frequent and lethal primary tumor of the brain. We have demonstrated that IRE1 is a key player in glioblastoma by conferring tumor cells specific aggressive features associated with remodeling of the tumor stroma (angiogenesis, immune infiltrate), tumor cell migration/invasion properties or cell plasticity. We are currently investigating if and how these processes are occurring through cross-talks with other signaling pathways. We are delineating as well the specificity and selectivity of IRE1 RNase-dependent molecular mechanism in cancer cells and developing new models to investigate in vitro and in vivo the impact of selectively regulating this enzymatic activity for therapeutic purposes.
Recent publications :
Lhomond S, Avril T, Dejeans N, Voutetakis K, Doultsinos D, McMahon M, Pineau R, Obacz J, Papadodima O, Jouan F, Bourien H, Logotheti M, Jégou G, Pallares-Lupon N, Schmit K, Le Reste PJ, Etcheverry A, Mosser J, Barroso K, Vauléon E, Maurel M, Samali A, Patterson JB, Pluquet O, Hetz C, Quillien V, Chatziioannou A, Chevet E. Dual IRE1 RNase functions dictate glioblastoma development. EMBO Mol Med. 2018 Mar;10(3):e7929.
Logue SE, McGrath EP, Cleary P, Greene S, Mnich K, Almanza A, Chevet E, Dwyer RM, Oommen A, Legembre P, Godey F, Madden EC, Leuzzi B, Obacz J, Zeng Q, Patterson JB, Jäger R, Gorman AM, Samali A. Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nat Commun. 2018 Aug 15;9(1):3267.
Le Reste PJ, Pineau R, Voutetakis K, Samal J, Jégou G, Lhomond S, Gorman AM, Samali A, Patterson JB, Zeng Q, Pandit A, Aubry M, Soriano N, Etcheverry A, Chatziioannou A, Mosser J, Avril T, Chevet E. Local intracerebral inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo. Cancer Lett. 2020 Dec 1;494:73-83.
Chemical biology approaches to modulate endoplasmic reticulum proteostasis
The objective of this project is to identify artificial modulators of the pathways described above. In particular we focus on the regulation of protein-protein interactions (PPi) and catalytic activities within the ER proteostasis network using in vitro, cell-based and in vivo approaches. This project is carried out in collaboration with LA Eriksson (U. Gothenburg, Sweden) (Figure 2).
Recent publications :
Raymundo DP, Doultsinos D, Guillory X, Carlesso A, Eriksson LA, Chevet E. Pharmacological Targeting of IRE1 in Cancer. Trends Cancer. 2020 Dec;6(12):1018-1030.
Doultsinos D, Carlesso A, Chintha C, Paton JC, Paton AW, Samali A, Chevet E, Eriksson LA. Peptidomimetic-based identification of FDA-approved compounds inhibiting IRE1 activity. FEBS J. 2021 Feb;288(3):945-960.