Pancreatic Cancer Cells Require the Transcription Factor MYRF to Maintain ER Homeostasis: Developmental Cell

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Abstract

Many tumors of endodermal origin are composed of highly secretory cancer cells that must adapt endoplasmic reticulum (ER) activity to enable proper folding of secreted proteins and prevent ER stress. We found that pancreatic ductal adenocarcinomas (PDACs) overexpress the myelin regulatory factor (MYRF), an ER membrane-associated transcription factor (TF) released by self-cleavage. MYRF was expressed in the well-differentiated secretory cancer cells, but not in the poorly differentiated quasi-mesenchymal cells that coexist in the same tumor. MYRF expression was controlled by the epithelial identity TF HNF1B, and it acted to fine-tune the expression of genes encoding highly glycosylated, cysteine-rich secretory proteins, thus preventing ER overload. MYRF-deficient PDAC cells showed signs of ER stress, impaired proliferation, and an inability to form spheroids in vitro, while in vivo they generated highly secretory but poorly proliferating and hypocellular tumors. These data indicate a role of MYRF in the control of ER homeostasis in highly secretory PDAC cells. Milan, Balestrieri et al. show that high secretory activity is a distinctive feature of well-differentiated pancreatic cancer cells. In this context, the ER-associated transcription factor MYRF, which is released by autocatalytic cleavage, maintains ER integrity and prevents ER stress. © 2020 Elsevier Inc.
Original languageEnglish
Pages (from-to)398
JournalDev. Cell
Volume55
Issue number4
DOIs
Publication statusPublished - 2020

Keywords

  • differentiation
  • ER stress
  • MYRF
  • pancreatic cancer
  • stress response
  • transcription
  • tumor heterogeneity
  • unfolded protein response

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