Journal article
Abstract A03: All the roads bring to Rome: How acetyl-CoA metabolism supports multistep pancreatic carcinogenesis
Cancer research (Chicago, Ill.), v 79(24_Supplement), pp A03-A03
15 Dec 2019
Abstract
Abstract Mutant KRAS is thought to initiate pancreatic tumorigenesis, orchestrating a program that leads to cell de-differentiation, proliferation, and symbiotic cooperation with neighboring cells, enabling the cancer cells to thrive in a particularly harsh microenvironment. Recent studies have highlighted the role of metabolites in regulating the epigenome. Although oncogenic KRAS is known to reprogram cellular metabolism, the role of metabolic control of the epigenome in pancreatic tumorigenesis is poorly understood. We showed that expression of KRASG12D in mouse pancreas promotes elevated histone acetylation levels in pancreatic acinar cells, and that this precedes tumor development. We hypothesized that augmented acetyl-CoA metabolism may play a role in facilitating pancreatic tumorigenesis. To test this, we generated mice deficient for Acly (acetyl-CoA producing enzyme) in pancreas (Pdx1-Cre; Aclyf/f mice). In the context of KRASG12D expression, ACLY deficiency reduces histone acetylation levels in pancreatic acinar cells and impairs formation of neoplastic lesions. ACLY deficiency also impairs pancreatitis-induced tumor development. In testing roles for acetyl-CoA-dependent processes in ADM, we found that targeting either histone acetylation by BET inhibition or cholesterol synthesis with statins suppressed tumor onset. In vivo, response to BET and cholesterol synthesis blockade is associated with recruitment of CD8+ T-cells. The findings indicate that ACLY-dependent metabolic and epigenetic remodeling promote tumor development and point to the potential to target acetyl-CoA metabolism for pancreatic cancer. Potential role of tumor-infiltrating leukocytic cells in modulating acetyl-CoA metabolism in vivo, cancer cell-autonomous mechanisms for acetyl-CoA levels regulation, as well as consequences for therapeutic targeting and dietary interventions, will be discussed. Citation Format: Alessandro Carrer, Sophie Trefely, Steven Zhao, Sydney Campbell, Yogev Sela, Simone Sidoli, Benjamin A. Garcia, Nathaniel W. Snyder, Ben Z. Stanger, Kathryn E. Wellen. All the roads bring to Rome: How acetyl-CoA metabolism supports multistep pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A03.
Metrics
9 Record Views
Details
- Title
- Abstract A03: All the roads bring to Rome: How acetyl-CoA metabolism supports multistep pancreatic carcinogenesis
- Creators
- Alessandro Carrer - Venetian Institute of Molecular MedicineSophie Trefely - University of Pennsylvania, Philadelphia PA.Steven Zhao - University of Pennsylvania, Philadelphia PA.Sydney Campbell - University of Pennsylvania, Philadelphia PA.Yogev Sela - University of Pennsylvania, Philadelphia PA.Simone Sidoli - University of Pennsylvania, Philadelphia PA.Benjamin A. Garcia - University of Pennsylvania, Philadelphia PA.Nathaniel W. Snyder - Drexel UniversityBen Z. Stanger - University of Pennsylvania, Philadelphia PA.Kathryn E. Wellen - University of Pennsylvania, Philadelphia PA.
- Publication Details
- Cancer research (Chicago, Ill.), v 79(24_Supplement), pp A03-A03
- Publisher
- American Association for Cancer Research (AACR)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000526416300003
- Other Identifier
- 991019167958504721
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology