RT Journal Article
SR Electronic
T1 PERK inhibition blocks metastasis initiation by limiting UPR-dependent survival of dormant disseminated cancer cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.30.454473
DO 10.1101/2021.07.30.454473
A1 Veronica Calvo
A1 Wei Zheng
A1 Kirk A. Staschke
A1 Julie Cheung
A1 Ana Rita Nobre
A1 Eduardo F. Farias
A1 Ari Nowacek
A1 Mark Mulvihill
A1 Alan C. Rigby
A1 Julio A. Aguirre-Ghiso
YR 2021
UL http://biorxiv.org/content/early/2021/07/30/2021.07.30.454473.abstract
AB The unfolded protein response (UPR) kinase PERK has been shown to serve as a survival factor for HER2-driven breast and prostate cancers as well as for dormant cancer cells. However, its role in metastasis is not understood. Here we found in the MMTV-HER2 mouse model that quiescent HER2+ disseminated cancer cells (DCCs) displayed unresolved ER stress as revealed by high expression of the PERK-inducible GADD34 gene. Single cell gene expression profiling and imaging confirmed that a significant proportion of DCCs in lungs were dormant and displayed an active UPR. In human breast cancer metastasis biopsies, GADD34 expression and quiescence were also positively correlated. Importantly, PERK inhibition with a specific inhibitor (HC4) blunted metastasis development by selectively killing UPRhigh quiescent but not proliferative DCCs. We also show that PERK inhibition altered optimal HER2 activity in primary tumors as a result of sub-optimal HER2 trafficking and phosphorylation in response to EGF. Our data identify PERK as a unique “Achilles heel” in dormant DTCs, supporting a requisite role for PERK in DTCs. Taken together, these data identify novel strategies to eliminate quiescent DCCs in patients with disseminated cancer disease.Competing Interest StatementJAAG is a scientific co-founder of, scientific advisory board member and equity owner in HiberCell and receives financial compensation as a consultant for HiberCell, a Mount Sinai spin-off company focused on therapeutics that prevent or delay cancer recurrence. VC, EFF, AN, MM and ACR are HiberCell employees.