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Pancreas
Original research
Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas
  1. Yuki Makino1,2,
  2. Kimal I Rajapakshe1,2,
  3. Benson Chellakkan Selvanesan1,2,
  4. Takashi Okumura1,2,
  5. Kenjiro Date1,2,
  6. Prasanta Dutta3,
  7. Lotfi Abou-Elkacem1,2,
  8. Akiko Sagara1,2,
  9. Jimin Min1,2,
  10. Marta Sans1,2,
  11. Nathaniel Yee1,2,
  12. Megan J Siemann1,2,
  13. Jose Enriquez3,
  14. Paytience Smith3,
  15. Pratip Bhattacharya3,
  16. Michael Kim4,
  17. Merve Dede5,
  18. Traver Hart5,6,
  19. Anirban Maitra1,2,
  20. Fredrik Ivar Thege1,2
  1. 1Translational Molecular Pathology, UTMDACC, Houston, Texas, USA
  2. 2Sheikh Ahmed Center for Pancreatic Cancer Research, UTMDACC, Houston, Texas, USA
  3. 3Cancer Systems Imaging, UTMDACC, Houston, Texas, USA
  4. 4Surgical Oncology, UTMDACC, Houston, Texas, USA
  5. 5Bioinformatics & Computational Biology, UTMDACC, Houston, Texas, USA
  6. 6Department of Cancer Biology, UTMDACC, Houston, Texas, USA
  1. Correspondence to Dr Fredrik Ivar Thege; fithege{at}mdanderson.org; Dr Yuki Makino; ymakino{at}mdanderson.org

Abstract

Background Oncogenic ‘hotspot’ mutations of KRAS and GNAS are two major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas-specific KrasG12D and GnasR201C co-expression in p48Cre; KrasLSL-G12D; Rosa26LSL-rtTA; Tg (TetO-GnasR201C) mice (‘Kras;Gnas’ mice) caused development of cystic lesions recapitulating IPMNs.

Objective We aim to unveil the consequences of mutant GnasR201C expression on phenotype, transcriptomic profile and genomic dependencies.

Design We performed multimodal transcriptional profiling (bulk RNA sequencing, single-cell RNA sequencing and spatial transcriptomics) in the ‘Kras;Gnas’ autochthonous model and tumour-derived cell lines (Kras;Gnas cells), where GnasR201C expression is inducible. A genome-wide CRISPR/Cas9 screen was conducted to identify potential vulnerabilities in KrasG12D;GnasR201C co-expressing cells.

Results Induction of GnasR201C—and resulting G(s)alpha signalling—leads to the emergence of a gene signature of gastric (pyloric type) metaplasia in pancreatic neoplastic epithelial cells. CRISPR screening identified the synthetic essentiality of glycolysis-related genes Gpi1 and Slc2a1 in KrasG12D;GnasR201C co-expressing cells. Real-time metabolic analyses in Kras;Gnas cells and autochthonous Kras;Gnas model confirmed enhanced glycolysis on GnasR201C induction. Induction of GnasR201C made KrasG12D expressing cells more dependent on glycolysis for their survival. Protein kinase A-dependent phosphorylation of the glycolytic intermediate enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was a driver of increased glycolysis on GnasR201C induction.

Conclusion Multiple orthogonal approaches demonstrate that KrasG12D and GnasR201C co-expression results in a gene signature of gastric pyloric metaplasia and glycolytic dependency during IPMN pathogenesis. The observed metabolic reprogramming may provide a potential target for therapeutics and interception of IPMNs.

  • pancreatic cancer
  • gastric metaplasia
  • glucose metabolism
  • pre-malignancy - GI tract
  • oncogenes

Data availability statement

Data are available in a public, open access repository. Bulk RNA-seq, single-cell RNA-seq and spatial transcriptomic datasets generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database under accession number GSE275406.

https://doi.org/10.1136/gutjnl-2024-332412

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    Data availability statement

    Data are available in a public, open access repository. Bulk RNA-seq, single-cell RNA-seq and spatial transcriptomic datasets generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database under accession number GSE275406.

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    Footnotes

    • X @FredrikThege

    • Correction notice This article has been corrected since it published Online First. The funding section has been updated.

    • Contributors Conceptualisation: YM, AM and FIT; methodology: YM, KIR, TH and PB; investigation: YM, BCS, TO, KD, PD, LA-E, AS, JM, MS, NY, MJS, JE, PS and MD; formal analysis and interpretation of data: YM, KIR, MD, AM and FIT; resources: MK and AM; writing—original draft: YM, AM and FIT; writing—review and editing: YM, AM and FIT; visualisation: YM, KIR and FIT; funding acquisition: AM; supervision: AM and FIT. AM is the guarantor of the project.

    • Funding AM is supported by the MD Anderson Pancreatic Cancer Moon Shot Programme, the Khalifa Bin Zayed Al-Nahyan Foundation and the NCI (U01CA200468, U54CA274371, and P50CA221707). FIT is supported by the Ben and Rose Cole Charitable PRIA Foundation. YM is supported by a Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowship. This research is supported in part by the MD Anderson Cancer Center Support Grant (P30CA016672). MS is a TRIUMPH Fellow in the CPRIT Training Program (RP210028).

    • Competing interests AM is listed as an inventor on a patent that has been licensed by Johns Hopkins University to Thrive Earlier Detection. AM serves as a consultant for Tezcat Biosciences.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.