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Journal article
Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis
Cancer discovery, v 9(3), pp 416-435
01 Mar 2019
PMID: 30626590
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis
- Creators
- Alessandro Carrer - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.Sophie Trefely - Drexel UniversitySteven Zhao - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.Sydney L. Campbell - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.Robert J. Norgard - University of PennsylvaniaKollin C. Schultz - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.Simone Sidoli - University of PennsylvaniaJoshua L. D. Parris - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.Hayley C. Affronti - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.Sharanya Sivanand - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.Shaun Egolf - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.Yogev Sela - University of PennsylvaniaMarco Trizzino - The Wistar InstituteAlessandro Gardini - The Wistar InstituteBenjamin A. Garcia - University of PennsylvaniaNathaniel W. Snyder - Drexel UniversityBen Z. Stanger - Drexel UniversityKathryn E. Wellen - Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
- Publication Details
- Cancer discovery, v 9(3), pp 416-435
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 20
- Grant note
- 1-18-PDF-144 / American Diabetes Association GM110174; AI118891; CA196539; R01CA174761; R01CA228339; R03HD092630; 1F31CA217070-01; F99CA222741; 4K00CA212455-03 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01AI118891 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) T32AR007465 / NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) Pennsylvania Department of Health R25-GM071745 / UPenn Baccalaureate Research Education fellowship P01CA196539 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R03HD092630 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) R25GM071745 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) 14-20-25-WELL / 2014 Pancreatic Cancer Action Network-AACR Career Development Award
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000460211700027
- Scopus ID
- 2-s2.0-85063444840
- Other Identifier
- 991019167984404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology