Endoplasmic Reticulum Stress Drives Latent Pancreatic Tumor Metastases

Patients with pancreatic ductal adenocarcinoma (PDAC) often relapse after surgical resection of the primary tumor due to metastatic colonization, which occurs prior to diagnosis. Immunity has been shown to prevent the outgrowth of quiescent disseminated cancer cells (DCC), which give rise to microscopic latent metastases. Having identified the presence of hepatic DCCs in livers from patients with PDAC and an autochthonous mouse model of PDAC, Pommier and colleagues generated a fluorescently labeled metastatic mouse PDAC cell line (mM1DTLB) that recapitulates human PDAC harboring hepatic DCCs and can be selectively ablated by treatment with diphtheria toxin (DT) to elucidate the mechanisms underlying disseminated tumor cell latency in PDAC. Intrasplenic injection of mM1DTLB into mice after the DT-mediated ablation of subcutaneous mM1DTLB tumors (“preimmunization”) resulted in the presence of single MHCI⁻/CK19⁻/ECAD⁻ DCCs and decreased macrometastases compared with mice that received only an intrasplenic injection of mM1DTLB. Depletion of CD4⁺ and CD8⁺ T cells in preimmunized mice after the appearance of DCCs resulted in the outgrowth of latent DCCs and MHCI⁺/CK19⁺ macrometastases. Small MHCI⁻/ECAD⁻ and CK19⁻ subpopulations of mM1DTLB cells grown in vitro phenotypically resembled DCCs in vivo, and injection of ECAD⁺, but not ECAD⁻, mM1DTLB cells resulted in the formation of macrometastases, suggesting that MHCI⁻/ECAD⁻ /CK19⁻ mM1DTLB cells are precursors of quiescent DCCs. Further, ECAD⁻ cells exhibited increased expression of genes related to the endoplasmic reticulum (ER) stress response, particularly the transcription factor CHOP, which was expressed by hepatic DCCs in preimmunized mice as well as mice and patients with PDAC; however, ECAD⁺ cells, human PDAC, and hepatic murine macrometastases exhibited increased activation of the IRE1a/XBP1 pathway, which is required to resolve ER stress, compared with ECAD⁻ cells and murine and human hepatic DCCs. These results describe the cell-autonomous mechanism by which disseminated PDAC cells enter quiescence and evade immune surveillance while maintaining the potential for PDAC outgrowth.

Pommier A, Anaparthy N, Memos N, Kelley ZL, Gouronnec A, Yan R, et al. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science 2018 May 17 [Epub ahead of print].

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