Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases

Pommier, A., Anaparthy, N., Memos, N., Kelley, Z. L., Gouronnec, A., Yan, R., Auffray, C., Albrengues, J., Egeblad, M., Iacobuzio-Donahue, C. A., Lyons, S. K., Fearon, D. T. (2018) Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science. ISSN 0036-8075

URL: https://www.ncbi.nlm.nih.gov/pubmed/29773669
DOI: 10.1126/science.aao4908

Abstract

The majority of patients with pancreatic ductal adenocarcinoma (PDA) develop metastatic disease after resection of their primary tumor. We found that livers from patients and mice with PDA harbor single, disseminated cancer cells (DCCs) lacking expression of cytokeratin-19 (CK19) and major histocompatibility complex class I (MHCI). We created a mouse model to determine how these DCCs develop. Intra-portal injection of immunogenic PDA cells into pre-immunized mice seeded livers only with single, non-replicating DCCs that were CK19(-) and MHCI(-) The DCCs exhibited an endoplasmic reticulum (ER) stress response but, paradoxically lacked both inositol-requiring enzyme 1alpha activation and expression of the spliced form of transcription factor XBP1 (XBP1s). Inducible expression of XBP1s in DCCs, in combination with T cell-depletion, stimulated the outgrowth of macro-metastatic lesions that expressed CK19 and MHCI. Thus, unresolved ER stress 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 > Fearon lab
CSHL labs > Lyons lab
CSHL labs > Egeblad lab
Depositing User: Matt Covey
Date Deposited: 25 May 2018 20:43
Last Modified: 25 May 2018 20:43
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36593

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