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PERK inhibition blocks metastasis initiation by limiting UPR-dependent survival of dormant disseminated cancer cells

Veronica Calvo, View ORCID ProfileWei Zheng, Kirk A. Staschke, Julie Cheung, Ana Rita Nobre, Eduardo F. Farias, Ari Nowacek, Mark Mulvihill, Alan C. Rigby, Julio A. Aguirre-Ghiso
doi: https://doi.org/10.1101/2021.07.30.454473
Veronica Calvo
1Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3HiberCell, Inc, 619 West 54th Street, 8th Floor, New York, NY USA
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Wei Zheng
1Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • ORCID record for Wei Zheng
Kirk A. Staschke
2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
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Julie Cheung
1Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Ana Rita Nobre
1Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Eduardo F. Farias
1Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3HiberCell, Inc, 619 West 54th Street, 8th Floor, New York, NY USA
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Ari Nowacek
3HiberCell, Inc, 619 West 54th Street, 8th Floor, New York, NY USA
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Mark Mulvihill
3HiberCell, Inc, 619 West 54th Street, 8th Floor, New York, NY USA
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Alan C. Rigby
3HiberCell, Inc, 619 West 54th Street, 8th Floor, New York, NY USA
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Julio A. Aguirre-Ghiso
1Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • For correspondence: julio.aguirre-ghiso@mssm.edu
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Abstract

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 Statement

JAAG 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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 30, 2021.
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PERK inhibition blocks metastasis initiation by limiting UPR-dependent survival of dormant disseminated cancer cells
Veronica Calvo, Wei Zheng, Kirk A. Staschke, Julie Cheung, Ana Rita Nobre, Eduardo F. Farias, Ari Nowacek, Mark Mulvihill, Alan C. Rigby, Julio A. Aguirre-Ghiso
bioRxiv 2021.07.30.454473; doi: https://doi.org/10.1101/2021.07.30.454473
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PERK inhibition blocks metastasis initiation by limiting UPR-dependent survival of dormant disseminated cancer cells
Veronica Calvo, Wei Zheng, Kirk A. Staschke, Julie Cheung, Ana Rita Nobre, Eduardo F. Farias, Ari Nowacek, Mark Mulvihill, Alan C. Rigby, Julio A. Aguirre-Ghiso
bioRxiv 2021.07.30.454473; doi: https://doi.org/10.1101/2021.07.30.454473

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