Pancreatic cancer cells require the transcription factor MYRF (Myelin Regulatory Factor) to maintain ER homeostasis (RNA-Seq).

Many tumors of endodermal origin are composed of highly secretory cancer cells that must adapt endoplasmic reticulum (ER) activity to enable proper folding of secretory proteins, prevent ER stress and thus maintain their viability. In pancreatic ductal adenocarcinoma (PDAC), well-differentiated and secretory cancer cells coexist with poorly differentiated cells with quasi-mesenchymal features. We found that the differentiated PDAC cells, but not the undifferentiated ones, expressed an ER membrane-associated transcription factor (TF), Myelin Regulatory Factor (MYRF), that is released by self-cleavage and translocates to the nucleus. MYRF expression was directly controlled by HNF1B, a TF maintaining epithelial identity in PDAC, and it acted to fine-tune the expression of genes encoding highly glycosylated and cysteine-rich secretory proteins, thus preventing ER overload. MYRF-deficient PDAC cells showed anatomical and biochemical signs of ER stress, impaired proliferation and inability to form spheroids in vitro, while in vivo they generated highly secretory but poorly proliferating and hypo-cellular tumors. These data indicate a role of MYRF in the control of homeostasis and proliferation of cancer cells with high secretory activity Total RNA from human pancreatic ductal adenocarcinoma cell lines was processed for multiparallel sequencing. Experiments were carried out in genome edited clonal CFPAC1 cells (3 MYRF-deleted CRISPR-Cas9 clones and 3 wt clones).