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.
Figure 1: Schematic representation of the Unfolded Protein Response. Purple signs represent IRE1-dependent pathways, blue signs represent PERK-dependent pathways and green signs represent ATF6-dependent signals. Orange signs represent the negative feedback loop activated downstream of PERK to dephosphorylate eIF2α and restore translation. UPR target functions are indicated in red. Dual color signs indicate the contribution to more that one pathway following the same color code as described above.