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Endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases

Arnaud Pommier, Naishitha Anaparthy, Nicoletta Memos, Z Larkin Kelley, Alizée Gouronnec, Jean Albrengues, Mikala Egeblad, Christine A. Iacobuzio-Donahue, Scott K. Lyons, Douglas T. Fearon
doi: https://doi.org/10.1101/187484
Arnaud Pommier
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Naishitha Anaparthy
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
4Department of Molecular and Cellular Biology, Stony Brook University, NY 11794
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Nicoletta Memos
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Z Larkin Kelley
2Weill Cornell Medicine, New York, NY 10065
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Alizée Gouronnec
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Jean Albrengues
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Mikala Egeblad
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Christine A. Iacobuzio-Donahue
3Memorial Sloan Kettering Cancer Center, New York, NY 10065
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Scott K. Lyons
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
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Douglas T. Fearon
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
2Weill Cornell Medicine, New York, NY 10065
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  • For correspondence: dfearon@cshl.edu
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Abstract

Patients who have had their primary pancreatic ductal adenocarcinoma (PDA) surgically resected often develop metastatic disease, exemplifying the problem of latent metastases. Livers from patients and mice with PDA contained single, disseminated cancer cells (DCCs) with an unusual phenotype of being cytokeratin-19 (CK19)- and MHC class I (MHCI)-. We created a mouse model to determine how DCCs develop, their relationship to metastatic latency, and the role of immunity. Intra-portal injection of immunogenic PDA cells into pre-immunized mice seeded livers only with single, non-replicating DCCs lacking MHCI and CK19; naïve recipients had macro-metastases. Transcriptomic analysis of PDA cells with the DCC phenotype demonstrated an endoplasmic reticulum (ER) stress response. Relieving ER stress with a chemical chaperone, in combination with T cell-depletion, stimulated outgrowth of macro-metastatic lesions containing PDA cells expressing MHCI and CK19. The ER stress response is the cell-autonomous reaction that enables DCCs to escape immunity and establish latent metastases.

One sentence summary: Latent pancreatic cancer metastases are created when T cells select disseminated cancer cells in which immune resistance and quiescence have been imposed by endoplasmic stress.

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Posted September 11, 2017.
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Endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases
Arnaud Pommier, Naishitha Anaparthy, Nicoletta Memos, Z Larkin Kelley, Alizée Gouronnec, Jean Albrengues, Mikala Egeblad, Christine A. Iacobuzio-Donahue, Scott K. Lyons, Douglas T. Fearon
bioRxiv 187484; doi: https://doi.org/10.1101/187484
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Endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases
Arnaud Pommier, Naishitha Anaparthy, Nicoletta Memos, Z Larkin Kelley, Alizée Gouronnec, Jean Albrengues, Mikala Egeblad, Christine A. Iacobuzio-Donahue, Scott K. Lyons, Douglas T. Fearon
bioRxiv 187484; doi: https://doi.org/10.1101/187484

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