Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis

Alessandro Carrer, Sophie Trefely, Steven Zhao, Sydney L. Campbell, Robert J. Norgard, Kollin C. Schultz, Simone Sidoli, Joshua L.D. Parris, Hayley C. Affronti, Sharanya Sivanand, Shaun Egolf, Yogev Sela, Marco Trizzino, Alessandro Gardini, Benjamin A. Garcia, Nathaniel W. Snyder, Ben Z. Stanger, Kathryn E. Wellen

Research output: Contribution to journalArticle

Abstract

Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in KRAS-mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specific loss of the acetyl-CoA–producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT–ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA–dependent processes exerts anticancer effects. SIGNIFICANCE : Pancreatic cancer is among the deadliest of human malignancies. We identify a key role for the metabolic enzyme ACLY, which produces acetyl-CoA, in pancreatic carcinogenesis. The data suggest that acetyl-CoA use for histone acetylation and in the mevalonate pathway facilitates cell plasticity and proliferation, suggesting potential to target these pathways.

Original languageEnglish (US)
Pages (from-to)416-435
Number of pages20
JournalCancer discovery
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

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Acetyl Coenzyme A
Carcinogenesis
ATP Citrate (pro-S)-Lyase
Acetylation
Histones
Acinar Cells
Mevalonic Acid
Metaplasia
Neoplasms
Adenocarcinoma
Cell Proliferation
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzymes
Pancreatic Neoplasms
Epigenomics
Pancreas
Intercellular Signaling Peptides and Proteins
Mutation
Growth

ASJC Scopus subject areas

  • Oncology

Cite this

Carrer, A., Trefely, S., Zhao, S., Campbell, S. L., Norgard, R. J., Schultz, K. C., ... Wellen, K. E. (2019). Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer discovery, 9(3), 416-435. https://doi.org/10.1158/2159-8290.CD-18-0567

Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. / Carrer, Alessandro; Trefely, Sophie; Zhao, Steven; Campbell, Sydney L.; Norgard, Robert J.; Schultz, Kollin C.; Sidoli, Simone; Parris, Joshua L.D.; Affronti, Hayley C.; Sivanand, Sharanya; Egolf, Shaun; Sela, Yogev; Trizzino, Marco; Gardini, Alessandro; Garcia, Benjamin A.; Snyder, Nathaniel W.; Stanger, Ben Z.; Wellen, Kathryn E.

In: Cancer discovery, Vol. 9, No. 3, 01.03.2019, p. 416-435.

Research output: Contribution to journalArticle

Carrer, A, Trefely, S, Zhao, S, Campbell, SL, Norgard, RJ, Schultz, KC, Sidoli, S, Parris, JLD, Affronti, HC, Sivanand, S, Egolf, S, Sela, Y, Trizzino, M, Gardini, A, Garcia, BA, Snyder, NW, Stanger, BZ & Wellen, KE 2019, 'Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis', Cancer discovery, vol. 9, no. 3, pp. 416-435. https://doi.org/10.1158/2159-8290.CD-18-0567
Carrer A, Trefely S, Zhao S, Campbell SL, Norgard RJ, Schultz KC et al. Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer discovery. 2019 Mar 1;9(3):416-435. https://doi.org/10.1158/2159-8290.CD-18-0567
Carrer, Alessandro ; Trefely, Sophie ; Zhao, Steven ; Campbell, Sydney L. ; Norgard, Robert J. ; Schultz, Kollin C. ; Sidoli, Simone ; Parris, Joshua L.D. ; Affronti, Hayley C. ; Sivanand, Sharanya ; Egolf, Shaun ; Sela, Yogev ; Trizzino, Marco ; Gardini, Alessandro ; Garcia, Benjamin A. ; Snyder, Nathaniel W. ; Stanger, Ben Z. ; Wellen, Kathryn E. / Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. In: Cancer discovery. 2019 ; Vol. 9, No. 3. pp. 416-435.
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AU - Trefely, Sophie

AU - Zhao, Steven

AU - Campbell, Sydney L.

AU - Norgard, Robert J.

AU - Schultz, Kollin C.

AU - Sidoli, Simone

AU - Parris, Joshua L.D.

AU - Affronti, Hayley C.

AU - Sivanand, Sharanya

AU - Egolf, Shaun

AU - Sela, Yogev

AU - Trizzino, Marco

AU - Gardini, Alessandro

AU - Garcia, Benjamin A.

AU - Snyder, Nathaniel W.

AU - Stanger, Ben Z.

AU - Wellen, Kathryn E.

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