Is metabolism involved in pancreatic carcinogenesis?
Can we target metabolism to prevent pancreatic cancer?
Pancreatic cancer is the deadliest among the most common types of human malignancies. In light of the limited effectiveness of the current therapeutic options, substantial benefits could be gained by improving our understanding of the factors that contribute to tumor onset, particularly for patients at elevated risk, with the hope of curtailing disease incidence and enhancing the opportunity to treat it early.
Impaired metabolism is a hallmark of cancer. In the lab, we study how altered metabolism contributes to cell transformation and disease initiation. We are interested in whether pharmacological or dietary interventions can impact the susceptibility to develop pancreatic cancer.
Pancreatic cancer is characterized by poor overall survival and few efficacious therapeutic interventions. One area that has offered significant scope for further exploration are the numerous metabolic disturbances in preclinical models of pancreatic cancer.
Given the relative hypoxia of the tumor microenvironment and the limited nutrient availability, pancreatic tumor cells undergo substantial metabolic rewiring. Several of these derangements lead to imbalances in metabolites, including S-adenosylmethionine (SAM), α-ketoglutarate (αKG), and acetyl-CoA that are crucial to the regulation of epigenetic landscapes. They are substrate (SAM, acetyl-CoA) or substrates (αKG) for enzymes that modify chromatin conformation and regulate gene expression. In particular, we demonstrated that the availability of acetyl-CoA influences histone acetyl-transferase (HATs) activity, dictates global levels of histone acetylation.
Of note, oncogenes actively reprogram both cell metabolism and epigenetics. Previously, we have demonstrated that pancreatic cancer initiation features abundant epigenetic reprogramming in the progression to neoplasia, and that the cytoplasmic enzyme ATP-citrate lyase (ACLY), which produces acetyl-CoA from citrate, is essential to the neoplastic process. In mouse models, Acly deletion diminishes the enhancement of histone acetylation that occurs in response to mutant KRAS.
Our long-term goals are to identify how metabolic rewiring impacts the epigenome to guide cell fate decisions or facilitate cancer initiation. We intend to define the contribution of acetyl-CoA generation to metabolic and epigenetic remodeling in a number of different contexts:
- Dissect the contribution of mitochondrial dynamics to epigenetic reprogramming in cancer
The role of mitochondria for the generation of acetyl-CoA, and the downstream effects on chromatin landscapes remain unknown. We study how changes in mitochondrial shape or localization impact acetyl-CoA flux and whether mitochondrial dynamics dictate epigenetic state in cancer.
- Role of mitochondrial cristae remodeling in pancreatic cancer progression
Mitochondria are functioning in cancer cells, but their activity is profoundly rewired. The underlying mechanism is not clear. We found that mitochondrial ultrastructure is altered early in pancreatic carcinogenesis. We are studying the impact of mitochondrial remodeling for carcinogenesis using mouse models of impaired cristae biogenesis.
- Determinants of citrate cataplerosis
Acetyl-CoA is generated by mitochondrial-derived citrate. The conversion is mediated by ACLY, which has been shown to be important for cell differentiation and stemness, both in physiological and pathological conditions. However, what determines efflux of citrate (cataplerosis) from mitochondria is not clear. Using histone acetylation and cell de-differentiation as read-outs, we are interrogating cellular metabolites that might regulate the fate of mitochondrial citrate.
- Molecular memory of inflammation
Inflammation increases the risk of pancreatic cancer onset, even several years after complete recovery. Combining single nucleus RNA/ATAC sequencing, mouse modeling and epigenomic profiling we are interrogating the metabolic determinants of pancreatic cancer susceptibility after recovery from acute inflammation.
- Dietary contribution to pancreatic carcinogenesis
Several unhealthy lifestyles are associated with increased pancreatic cancer risk, but the role of diet is still somehow debated. We are examining the role of dietary fructose to pancreatic cancer predisposition and interrogating possible mechanisms, with a focus on fructose-derived acetate and protein acetylation.
- Cholesterol homeostasis and signaling in pancreatitis and pancreatic cancer progressions
De novo sterol synthesis is elevated in pancreatic cancer cells. Moreover, its cholesterol homeostasis is deregulated in tumor-initiating pancreatitis. We found that cholesterol supplementation promotes metaplasia of pancreatic acinar cells. We are currently investigating how dysregulation of cholesterol availability activates intracellular signaling and supports extracellular inflammation.
- Metabolic-dependent histone acetylation in B cell pathophysiology
Histone acetylation is enhanced in B cell germinal centers and derived leukemias. This is amenable to therapeutic strategies, but the contribution of metabolism and its role in modifying therapy response is unclear. In collaboration with the groups of F. Piazza and G. Semenzato, and leveraging our orthogonal expertise, we are studying the role of ACLY in B cell differentiation and proliferation in health and disease.
Carlotta Paoli
PhD student
Marco Fantuz
postdoc
Martina Spacci
Research Specialist
Beatrice Caciolari
Research Specialist
Arianna Picco
Undergrad
Noemi Inglese
Undergrad
- Zhao S, Jang C, Liu J, Uehara K, Gilbert M, Izzo L, Zeng X, Trefely S, Fernandez S, Carrer A, Miller KD, Schug ZT, Snyder NW, Gade TP, Titchenell PM, Rabinowitz JD, Wellen KE. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature. 2020 Mar;579(7800):586-591
- Sidoli S, Trefely S, Garcia BA, Carrer A. Integrated Analysis of Acetyl-CoA and Histone Modification via Mass Spectrometry to Investigate Metabolically Driven Acetylation. Methods Mol Biol. 2019;1928:125-147.
- 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. Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis. Cancer Discov. 2019 Mar;9(3):416-435.
- Sidoli S, Trefely S, Garcia BA, Carrer A. Integrated Analysis of Acetyl-CoA and Histone Modification via Mass Spectrometry to Investigate Metabolically Driven Acetylation. Methods Mol Biol. 2019;1928:125-147.
- Lee JV, Berry CT, Kim K, Sen P, Kim T, Carrer A, Trefely S, Zhao S, Fernandez S, Barney LE, Schwartz AD, Peyton SR, Snyder NW, Berger SL, Freedman BD, Wellen KE. Acetyl-CoA promotes glioblastoma cell adhesion and migration through Ca2+-NFAT signaling. Genes Dev. 2018 Apr 1;32(7-8):497-511.
- Carrer A, Leparulo A, Crispino G, Ciubotaru CD, Marin O, Zonta F, Bortolozzi M. Cx32 hemichannel opening by cytosolic Ca2+ is inhibited by the R220X mutation that causes Charcot-Marie-Tooth disease. Hum Mol Genet. 2018 Jan 1;27(1):80-94
- McDonald OG, Li X, Saunders T, Tryggvadottir R, Mentch SJ, Warmoes MO, Word AE, Carrer A, Salz TH, Natsume S, Stauffer KM, Makohon-Moore A, Zhong Y, Wu H, Wellen KE, Locasale JW, Iacobuzio-Donahue CA, Feinberg AP. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet. 2017 Mar;49(3):367-376.
- Carrer A, Parris JL, Trefely S, Henry RA, Montgomery DC, Torres A, Viola JM, Kuo YM, Blair IA, Meier JL, Andrews AJ, Snyder NW, Wellen KE. Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels J Biol Chem. 2017 Feb 24;292(8):3312-3322.
- Carrer A, Wellen KE. Metabolism and epigenetics: a link cancer cells exploit. Curr Opin Biotechnol. 2015 Aug;34:23-9.
- Lee JV, Carrer A, Shah S, Snyder NW, Wei S, Venneti S, Worth AJ, Yuan ZF, Lim HW, Liu S, Jackson E, Aiello NM, Haas NB, Rebbeck TR, Judkins A, Won KJ, Chodosh LA, Garcia BA, Stanger BZ, Feldman MD, Blair IA, Wellen KE. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 2014 Aug 5;20(2):306-319.
- Carrer A, Lee JV, Shah S, Snyder NW, Wei S, Venneti S, Worth AJ, Yuan ZF, Lim HW, Liu S, Jackson E, Aiello NM, Haas NB, Rebbeck TR, Judkins A, Won KJ, Chodosh LA, Garcia BA, Stanger BZ, Feldman MD, Blair IA, Wellen KE, Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation, Cell Metab. 2014 Aug 5;20(2):306-19
- Carrer A, Wellen KE, Metabolism and epigenetics: a link cancer cells exploit, Curr Opin Biotechnol. 2014 Nov 29;34C:23-29
- Alessandro Carrer, Joshua L. D. Parris, Sophie Trefely, Ryan A. Henry, David Montgomery, Yin-Ming Kuo, Ian A. Blair, Jordan L. Meier, Andrew J. Andrews, Nathaniel W. Snyder, and Kathryn E. Wellen, Impact of high fat diet on tissue acyl-CoA and histone acetylation levels, Journal of Biological Chemistry, 2017
- Oliver McDonald, Tyler Saunders, Rakel Tryggvadottir, Samantha Mentch, Marc Warmoes, Anna Word, Alessandro Carrer, Tal Salz, Sonoko Natsume, Kimberly Stauffer, Alvin Makohon-Moore, Yi Zhong, Hao Wu , Kathryn E Wellen , Jason Locasale , Christine Iacobuzio-Donahue, Xin Li, Large-scale epigenomic reprogramming links anabolic glucose metabolism to distant metastasis during the evolution of pancreatic cancer progression, Nature Genetics, 2017
- Paoli C & Carrer A*, Organotypic culture of acinar cells for the study of pancreatic carcinogenesis, Cancers, 2020
- Grisan F, Spacci M, Paoli C, Costamagna A, Fantuz M, Martini M, Lefkimmiatis K, Carrer A*, Cholesterol activates Cyclic AMP signaling in metaplastic acinar cells, Metabolites, 2021
ALESSANDRO CARRER
- Group Leader, Veneto Institute for Molecular Medicine (VIMM), Padua (2019)
- Research Associate, University of Pennsylvania, Philadelphia, PA (2019)
- Postdoctoral fellow, University of Pennsylvania, Philadelphia, PA (2017)
- Postdoctoral fellow, Intern. Center for Genetic Engineering and Biotechnology (ICGEB), Trieste (2012)
- PhD Student, International Center for Genetic Engineering and Biotechnology (ICGEB), Trieste (2010)
Selected Awards
- iCARE-2 Fellowship Award , AIRC-MSCA (2019)
- Seal of Excellence, Marie Sklodowska-Curie Actions, H2020 (2019)
- Travel Award, International Society for Cancer Metabolism, ISCaM (2018)
- Scholar-In-Training Award, AACR (2011)
- Scholar-In-Training Award, MRS-AACR (2010)
- “AtaxiaUK” long-term fellowship, Ataxia UK (2008)
Current funding
- My First AIRC Grant (AIRC)
- WorldWide Cancer Foundation
- Marie-Curie MSCA Individual Fellowship