Pommier, Arnaud, Anaparthy, Naishitha, Memos, Nicoletta, Kelley, Larkin, Gouronnec, Alizée, Albrengues, Jean, Egeblad, Mikala, Iacobuzio-Donahue, Christine, Lyons, Scott, Fearon, Douglas (2017) Endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science. (Submitted)
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.
| Item Type: | Paper |
|---|---|
| Subjects: | organs, tissues, organelles, cell types and functions > organelles, types and functions > endoplasmic reticulum diseases & disorders > cancer > metastasis diseases & disorders > cancer > cancer types > pancreatic cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Egeblad lab CSHL labs > Fearon lab CSHL labs > Lyons lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2017 |
| Date Deposited: | 13 Oct 2023 18:03 |
| Last Modified: | 21 Dec 2023 16:11 |
| PMCID: | PMC6547380 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41262 |
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