气候变化领域集成服务门户(CCPortal): Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

CCPortal

DOI	10.1073/pnas.2003014118
	Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1
	Tsai P.-Y.; Lee M.-S.; Jadhav U.; Naqvi I.; Madha S.; Adler A.; Mistry M.; Naumenko S.; Lewis C.A.; Hitchcock D.S.; Roberts F.R.; DelNero P.; Hank T.; Honselmann K.C.; Oyarvide V.M.; Mino-Kenudson M.; Clish C.B.; Shivdasani R.A.; Kalaany N.Y.
发表日期	2021
ISSN	00278424
卷号	118 期号:10
英文摘要	Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify nongenetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Epigenetics; Glutamine synthetase; Mtorc1; Nutrient deprivation; Pancreatic cancer
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180361
作者单位	Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, United States; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, United States; Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, United States; Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, United States; Department of Medicine, Harvard Medical School, Boston, MA 02115, United States; Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, MA 02115, United States; Metabolite Profiling Core Facility, Whitehead Institute for Biomedical Research, Cambridge, MA 02142, United States; Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States; FUJIFILM VisualSonics Inc., Toronto, ON M4N 3N1, Canada; Cancer Prevention Fellowship Pr...
推荐引用方式 GB/T 7714	Tsai P.-Y.,Lee M.-S.,Jadhav U.,et al. Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1[J],2021,118(10).
APA	Tsai P.-Y..,Lee M.-S..,Jadhav U..,Naqvi I..,Madha S..,...&Kalaany N.Y..(2021).Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1.Proceedings of the National Academy of Sciences of the United States of America,118(10).
MLA	Tsai P.-Y.,et al."Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1".Proceedings of the National Academy of Sciences of the United States of America 118.10(2021).