Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 398 |
| Journal | Dev. Cell |
| Volume | 55 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2020 |
Keywords
- differentiation
- ER stress
- MYRF
- pancreatic cancer
- stress response
- transcription
- tumor heterogeneity
- unfolded protein response
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Pancreatic Cancer Cells Require the Transcription Factor MYRF to Maintain ER Homeostasis : Developmental Cell. / Milan, M.; Balestrieri, C.; Alfarano, G.; Polletti, S.; Prosperini, E.; Nicoli, P.; Spaggiari, P.; Zerbi, A.; Cirulli, V.; Diaferia, G.R.; Natoli, G.
In: Dev. Cell, Vol. 55, No. 4, 2020, p. 398.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Pancreatic Cancer Cells Require the Transcription Factor MYRF to Maintain ER Homeostasis
T2 - Developmental Cell
AU - Milan, M.
AU - Balestrieri, C.
AU - Alfarano, G.
AU - Polletti, S.
AU - Prosperini, E.
AU - Nicoli, P.
AU - Spaggiari, P.
AU - Zerbi, A.
AU - Cirulli, V.
AU - Diaferia, G.R.
AU - Natoli, G.
N1 - Export Date: 4 March 2021 CODEN: DCEEB Correspondence Address: Diaferia, G.R.; Department of Experimental Oncology, Italy; email: giuseppe.diaferia@ieo.it Correspondence Address: Natoli, G.; Department of Experimental Oncology, Italy; email: gioacchino.natoli@ieo.it Funding details: 20251, 5×1000 Funding details: GR-2016-02361721 Funding details: 30 EY001730 Funding details: National Institutes of Health, NIH, R01 DK103711, R01DK121275 Funding details: University of Washington, UW Funding details: Juvenile Diabetes Research Foundation Australia, 2-SRA-2019-836-S-B Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC Funding text 1: This study was supported by AIRC , the Italian Association for Research on Cancer (AIRC Investigator grant 20251 to G.N. and AIRC 5×1000 Grant ISM) and by the Italian Ministry of Health (grant GR-2016-02361721 to G.R.D.). This work was also partially supported by the Italian Ministry of Health with “Ricerca Corrente” and 5×1000 funds. V.C. was supported by NIH grants R01 DK103711 and R01DK121275, by a Juvenile Diabetes Research Foundation grant 2-SRA-2019-836-S-B. Transmission electron microscopy was performed with the expert assistance of Edward Parker and Dale E. Cunningham at the Vision Science Center, University of Washington (Seattle, WA) supported by NIH NEI Center Core Grant #P30 EY001730. 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PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - differentiation
KW - ER stress
KW - MYRF
KW - pancreatic cancer
KW - stress response
KW - transcription
KW - tumor heterogeneity
KW - unfolded protein response
U2 - 10.1016/j.devcel.2020.09.011
DO - 10.1016/j.devcel.2020.09.011
M3 - Article
VL - 55
SP - 398
JO - Dev. Cell
JF - Dev. Cell
SN - 1534-5807
IS - 4
ER -