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Harvard Medical School, Boston Children’s Hospital

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Proc. Natl. Acad. Sci. USA, March 9, 2021 118 (10) e2003014118 | https://doi.org/10.1073/pnas.2003014118 Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

Pei-Yun Tsai^a,b,1, Min-Sik Lee^a,b,c,1, Unmesh Jadhav^d,e,f,g, Insia Naqvi^a, Shariq Madha^d,e, Ashley Adler^a,c, Meeta Mistry^h, Sergey Naumenko^h, Caroline A. Lewisⁱ, Daniel S. Hitchcock^j, Frederick R. Roberts^k, Peter DelNero^a,l, Thomas Hank^m, Kim C. Honselmann^m, Vicente Morales Oyarvide^d, Mari Mino-Kenudsonⁿ, Clary B. Clish^j, Ramesh A. Shivdasani^d,e,f,g,o, and Nada Y. Kalaany^a,b,c,2

^aDivision of Endocrinology, Boston Children’s Hospital, Boston, MA 02115;
^bDepartment of Pediatrics, Harvard Medical School, Boston, MA 02115;
^cBroad Institute of MIT and Harvard, Cambridge, MA 02142;
^dDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
^eCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215;
^fDepartment of Medicine, Brigham and Women’s Hospital, Boston, MA 02115;
^gDepartment of Medicine, Harvard Medical School, Boston, MA 02115;
^hBioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, MA 02115;
ⁱMetabolite Profiling Core Facility, Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
^jMetabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142;
^kFUJIFILM VisualSonics Inc., Toronto, ON M4N 3N1, Canada;
^lCancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892;
^mDepartment of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
ⁿDepartment of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
^oHarvard Stem Cell Institute, Cambridge, MA 02138

¹P.-Y.T. and M.-S.L. contributed equally to this work.

²To whom correspondence may be addressed.

Abstract

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.

논문정보

형식Research article
게재일2021년 03월 (BRIC 등록일 2021-03-31)
연구진국외 연구진
분야 생명과학 > 생화학

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