Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases.
Fiche publication
Date publication
juin 2018
Journal
Science (New York, N.Y.)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr POMMIER Arnaud
Tous les auteurs :
Pommier A, Anaparthy N, Memos N, Kelley ZL, Gouronnec A, Yan R, Auffray C, Albrengues J, Egeblad M, Iacobuzio-Donahue CA, Lyons SK, Fearon DT
Lien Pubmed
Résumé
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.
Mots clés
Animals, Carcinoma, Pancreatic Ductal, immunology, Endoplasmic Reticulum Stress, immunology, Endoribonucleases, genetics, Genes, MHC Class I, Genetic Engineering, Humans, Keratin-19, metabolism, Liver Neoplasms, immunology, Lymphocyte Depletion, Mice, Mice, Inbred C57BL, Neoplasms, Experimental, genetics, Pancreatic Neoplasms, immunology, Protein Serine-Threonine Kinases, genetics, T-Lymphocytes, immunology, Tumor Escape, X-Box Binding Protein 1, genetics
Référence
Science. 2018 06 15;360(6394):