期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2003014118
关键词
pancreatic cancer; nutrient deprivation; epigenetics; mTORC1; glutamine synthetase
资金
- American Cancer Society Research Scholar Grant [RSG-17-070-01-TBG]
- Boston Children's Hospital
- NIH/National Cancer Institute [R01 CA211944]
- Top University Strategic Alliance fellowship from Taiwan
- Harvard Catalyst, the Harvard Clinical and Translational Science Center (NIH) [UL1 RR 025758]
- Harvard Medical School Research Computing Group
Under limiting levels of both glucose and glutamine, adapted clonal human PDA cells show enhanced growth and tumor-forming capacity, likely through mechanisms involving amino acid synthesis for de novo glutamine and nucleotide synthesis. Additionally, adapted clones also display enhanced mTORC1 activity.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据