ASIP outstanding investigator award lecture
Endoplasmic Reticulum Stress Signaling in Cancer Cells

https://doi.org/10.1016/j.ajpath.2020.01.010Get rights and content
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To survive, cancer cells must resist numerous internal and environmental insults associated with neoplasia that jeopardize proteostasis within the endoplasmic reticulum (ER). Solid and hematopoietic tumors often experience genomic instability, oncogene activation, increased protein secretion demands, and somatic mutations in proteins handled by the secretory pathway that impede their folding. Invasion or metastasis into foreign environments can expose tumor cells to hypoxia, oxidative stress, lack of growth signals, inadequate amino acid supplies, glucose deprivation, and lactic acidosis, all of which pose challenges for protein processing in the ER. Together, these conditions can promote the buildup of misfolded proteins in the ER to cause ER stress, which then activates the unfolded protein response (UPR). An intracellular signaling network largely initiated by three ER transmembrane proteins, the UPR constantly surveils protein folding conditions within the ER lumen and when necessary initiates counteractive measures to maintain ER homeostasis. Under mild or moderate levels of ER stress, the homeostatic UPR sets in motion transcriptional and translational changes that promote cell adaption and survival. However, if these processes are unsuccessful at resolving ER stress, a terminal UPR program dominates and actively signals cell suicide. This article summarizes the mounting evidence that cancer cells are predisposed to ER stress and vulnerable to targeted interventions against ongoing UPR signaling.

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Supported by NIH grants R01CA219815 and R01EY027810.

Disclosures: S.A.O. is a founder, equity holder, and consultant for OptiKIRA, LLC (Cleveland, OH) and a consultant for Kezar Life Sciences (South San Francisco, CA).

S.A.O. is the 2019 recipient of the American Society for Investigative Pathology Outstanding Investigator Award, which is presented annually to a midcareer investigator with demonstrated excellence in research in experimental pathology. Portions of this work were presented at the 2018 Pathobiology for Investigators, Students, and Academicians scientific meeting, held at the University of Michigan, Ann Arbor, MI, on October 20–22, 2018, where S.A.O. delivered the Outstanding Investigator Award lecture.