Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases Journal Article
| Authors: | 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. |
| Article Title: | Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases |
| 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. 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 1a 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. 2017 © The Authors. |
| Keywords: | genetics; liver neoplasms; pancreatic neoplasms; t lymphocyte; t-lymphocytes; mouse; animal; metabolism; animals; mice; gene; mus; x box binding protein 1; carcinoma, pancreatic ductal; pathology; protein serine threonine kinase; mice, inbred c57bl; c57bl mouse; pancreas carcinoma; immunology; genetic engineering; protein-serine-threonine kinases; liver tumor; pancreas tumor; neoplasms, experimental; experimental neoplasm; cytokeratin 19; lymphocyte depletion; endoribonucleases; ribonuclease; keratin-19; secondary; tumor escape; endoplasmic reticulum stress; genes, mhc class i; humans; human; ern1 protein, mouse; xbp1 protein, mouse; x-box binding protein 1 |
| Journal Title: | Science |
| Volume: | 360 |
| Issue: | 6394 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2018-06-15 |
| Start Page: | eaao4908 |
| Language: | English |
| DOI: | 10.1126/science.aao4908 |
| PUBMED: | 29773669 |
| PROVIDER: | scopus |
| PMCID: | PMC6547380 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2019 -- Source: Scopus |
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