Stromal cues regulate the pancreatic cancer epigenome and metabolome
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Significance: Stromal fibroblasts of the pancreatic tumor microenvironment (TME) have been shown to play both tumor-supportive and tumor-suppressive roles in enacting a dysregulated wound-healing response. This apparent complexity suggests that an improved understanding of the molecular basis of cell–cell interactions in the TME is required to identify and target stroma-derived, growth-permissive mechanisms. Here we show that stromal cues induce transcriptional and metabolic changes in pancreatic cancer cells implicated in anabolic metabolism, which overlap with those previously demonstrated downstream of oncogenic Kras. Stromal signals broadly induce histone acetylation in the pancreatic cancer epigenome, and we highlight inhibition of acetyl-lysine sensing by the bromodomain and extraterminal (BET) bromodomain family, Bromodomain-containing protein 2 (BRD2) in particular, as a potential therapeutic strategy.
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Extracellular asparagine from serum and produced by a constitutively active integrated stress response in subpopulations of PDAC cells can be targeted using asparaginase, sensitizing PDAC tumors to mitochondrial inhibition in preclinical models.
“extracellular asparagine from serum and produced by a constitutively active integrated stress response in subpopulations of PDAC cells can be targeted using asparaginase, potently sensitizing PDAC tumors to mitochondrial inhibition in pre-clinical models239,246.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [246]
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- Chromatin Immunoprecipitation and ChIP-Seq. For ChIP and ChIP-Seq experi- ments under astromal and stromal conditions, 3D cultures were constructed using the PEGSSDA cross-linker to facilitate rapid dissociation. ChIP, deep sequencing, and analysis were performed as described previously (35). For additional details, see SI Materials and Methods. Orthotopic Transplant Studies. The p53 2.1.1 luciferase-expressing PDAC cell line was used for orthotopic transplantation into immune-competent FVB/n hosts, as previously described (45). All mouse experiments were performed with the approval of the institutional animal care and use committee (IACUC) of the Salk Institute. For further details, see SI Materials and Methods. ACKNOWLEDGMENTS. We thank P. Phojanakong, D. Wang, J. Alvarez, and H. Juguilon for technical assistance; J. Bradner for providing JQ1; and H. Stoppler and the UCSF Helen Diller Family Comprehensive Cancer Center Tissue Core for providing fresh-frozen human PDAC samples. This work was funded by NIH Grants DK057978, HL105278, DK090962, HL088093, ES010337, and CA014195 (to R.M.E.), K99CA188259 (to M.H.S.), and R01GM095567 (to A.C.K.); National Cancer Institute Grants R01CA15749, R01CA188048, and P01CA117969; ACS Research Scholar Grant RSG-13-298- 01-TBG; the Glenn Foundation for Medical Research; · DOI
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- Authors
- Sherman, M. H., Yu, R. T., Tseng, T. W., Sousa, C. M., Liu, S., Truitt, M. L., He, N., Ding, N., Liddle, C., Atkins, A. R., Leblanc, M., Collisson, E. A., Asara, J. M., Kimmelman, A. C., Downes, M., & Evans, R. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215;
- The University of Sydney (AU)
- University of California, San Francisco (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-01-17
- Volume
- 114
- Issue
- 5
- Pages
- 1129-1134
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5293019
- OpenAlex
- W2579216462
- Cited by
- 147
- References
- 58
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 8 · 2023: 12 · 2022: 17 · 2021: 15 · 2020: 22 · 2019: 24 · 2018: 25 · 2017: 4
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (DK057978, HL105278, DK0909062, HL088093, ES010337, CA014195, K99CA188259)
- Glenn Foundation for Medical Research (Evans)
- Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002)
- American Association for Cancer Research (SU2C-AACR-DT0509)
- Howard Hughes Medical Institute (Evans)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- pancreatic ductal adenocarcinoma, tumor microenvironment, cancer-associated fibroblasts, KRAS oncogenic signaling, histone acetylation, epigenome, tumor metabolome, BET proteins, BRD2, transcriptional regulation, tumor progression
- MeSH terms
- Bromodomain Containing Proteins, Acetylation, Energy Metabolism, Enhancer Elements, Genetic, Fibroblasts, Humans, Neoplasm Proteins, Pancreatic Neoplasms, Promoter Regions, Genetic, Transcription Factors, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Cytokines, Stromal Cells, Protein Serine-Threonine Kinases, Carcinoma, Pancreatic Ductal, Intercellular Signaling Peptides and Proteins, Histone Code, Metabolome, Pancreatic Stellate Cells, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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