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Science. 2018 Jun 15;360(6394). pii: eaao4908. doi: 10.1126/science.aao4908. Epub 2018 May 17.

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

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Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Department of Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA.
Weill Cornell Medicine, New York, NY 10065, USA.
Institut Cochin, Paris Descartes Université, CNRS UMR8104, INSERM U1016, 75014 Paris, France.
Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.


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. Intraportal injection of immunogenic PDA cells into preimmunized mice seeded livers only with single, nonreplicating DCCs that were CK19- and MHCI- The DCCs exhibited an endoplasmic reticulum (ER) stress response but paradoxically lacked both inositol-requiring enzyme 1α 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 macrometastatic lesions that expressed CK19 and MHCI. Thus, unresolved ER stress enables DCCs to escape immunity and establish latent metastases.

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