Pancreatic neuroendocrine tumors (PanNETs) are one class of solid tumor that may be particularly sensitive to protein folding stress due to their high secretory activity. The Oakes laboratory has evidence that the UPR is upregulated and required for PanNET growth. Based on these data, they will test whether PanNETs are reliant on elevated levels of Homeostatic UPR signaling to avoid the toxic effects of protein folding stress, and if targeted interventions to either reduce Homeostatic UPR outputs or alternatively trigger the Terminal UPR will have potent antitumor effects on the growth of PanNET cells in murine xenograft models
The unfolded protein response (UPR) is an intracellular signaling pathway largely controlled by two ER transmembrane kinases—IRE1a and PERK—that communicate the protein folding status of the endoplasmic reticulum (ER) to the nucleus in order to maintain homeostasis within this organelle. Hypoxia, nutrient deprivation, proteasome dysfunction, or sustained demands on the secretory pathway, conditions often encountered by solid tumor cells, lead to the accumulation of misfolded proteins in the ER and cause “ER stress.” Under remediable levels of ER stress, the UPR activates transcriptional and translational changes that promote adaptation (Homeostatic UPR). But when confronted with irremediable levels of ER stress, these adaptive measures fail, and the UPR instead switches strategies to trigger cell death (Terminal UPR).
Hiniker A, Oakes SA, Rao RC. Bilateral choroidal metastases from pancreatic adenocarcinoma. Ophthalmology. 2017;124(12):1825.
Oakes SA. Endoplasmic reticulum proteostasis: a key checkpoint in cancer. Am J Physiol Cell Physiol. 2016;312(2):C93-C102. doi: 10.11doi: 10.1016/j.ophtha.2017.08.02052/ajpcell.00266.2016
Hetz C, Chevet E, Oakes SA. Proteostasis control by the unfolded protein response. Nat Cell Biol. 2015 Jul; 17(7): 829–838. doi: 10.1038/ncb3184