Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases Academic Article uri icon

Overview

MeSH Major

  • Cellular Reprogramming
  • Immunity
  • Interleukin-6
  • Pancreatic Neoplasms

abstract

  • © The Author(s) 2017. 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 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 macro-metastatic lesions that expressed CK19 and MHCI. Thus, unresolved ER stress enables DCCs to escape immunity and establish latent metastases.

publication date

  • May 17, 2018

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1126/science.aao4908

PubMed ID

  • 29773669

Additional Document Info

start page

  • 1

end page

  • 15