Alessandro Carrer

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  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.

  Background

  Research

  Group Members

  Key Publications

  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.

  

  The role of mitochondrial for the generation of acetyl-CoA, and the downstream effects of mutant KRAS-induced acetyl-CoA on chromatin landscapes remain unknown.

  Our long-term goals are to identify how metabolic rewiring impacts the epigenome to facilitate alterations to cell fate in cancer. We intend to utilize acetyl-CoA to define the mitochondrial-to-nuclear connections that control epigenetic reprogramming in pancreatic cancer initiation. Our aims are to elucidate (1) the mechanisms by which mitochondrial function controls the availability of exported citrate and nucleo-cytoplasmic acetyl-CoA, and (2) the global effect of alterations in acetyl-CoA abundance on the epigenome and preneoplastic cell fate.

  We utilize acinar explants in vitro and lineage-traced mouse models of acinar-derived neoplasia to interrogate the chromatin accessibility and histone acetylation dynamics induced by alterations to acetyl-CoA.

  Mitochondria are key effectors of KRAS-triggered tumorigenesis. We study whether environmental factors impact mitochondrial structure or function and whether this increases the risk for pancreatic cancer later in life.

   

  

  Carlotta Paoli

  PhD student

  

  Marco Fantuz

  postdoc

  

  Martina Spacci

  Research Specialist

  

  Alessia Atella

  Research Specialist

  

  Thauan Serafini

  Undergrad

  1. 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
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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
  7. Sivanand S, Rhoades S, Jiang Q, Lee JV, Benci J, Zhang J, Yuan S, Viney I, Zhao S, Carrer A, Bennett MJ, Minn AJ, Weljie AM, Greenberg RA, Wellen KE. Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination. Mol Cell. 2017 Jul 20;67(2):252-265.e6.
  8. 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.
  9. 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.
  10. Zhao S, Torres A, Henry RA, Trefely S, Wallace M, Lee JV, Carrer A, Sengupta A, Campbell SL, Kuo YM, Frey AJ, Meurs N, Viola JM, Blair IA, Weljie AM, Metallo CM, Snyder NW, Andrews AJ, Wellen KE. ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch. Cell Rep. 2016 Oct 18;17(4):1037-1052.
  11. Carrer A, Wellen KE. Metabolism and epigenetics: a link cancer cells exploit. Curr Opin Biotechnol. 2015 Aug;34:23-9.
  12. 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.
  13. Carrer A, Moimas S, Zacchigna S, Pattarini L, Zentilin L, Ruozi G, Mano M, Sinigaglia M, Maione F, Serini G, Giraudo E, Bussolino F, Giacca M, Neuropilin-1 identifies a subset of Gr1- monocytes that can induce tumor vessel normalization and inhibit tumor growth, Cancer Res, 2012, Dec 15; 72(24)
  14. 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
  15. Carrer A, Wellen KE, Metabolism and epigenetics: a link cancer cells exploit, Curr Opin Biotechnol. 2014 Nov 29;34C:23-29
  16. Kazemi M, Carrer A, Moimas S, Zandonà L, Bussani R, Casagranda B, Palmisano S, Prelazzi P, Giacca M, Zentilin L, De Manzini N, Giacca M, Zacchigna S., VEGF121 and VEGF165 differentially promote vessel maturation and tumor growth in mice and humans, Cancer Gene Ther. 2016 Apr 1. doi: 10.1038/cgt.2016.12.
  17. Zhao, A. Torres, R. Henry, S. Trefely, M. Wallace, J.V. Lee, A. Carrer, A. Sengupta, S.L. Campbell, Y-M. Kuo, A.J. Frey, N. Meurs, J.M. Viola, I.A. Blair, A.M. Weljie, C.M. Metallo, N.W. Snyder, Andrew J. Andrews, Kathryn E. Wellen, ATP-citrate lyase controls a glucose-to-acetate metabolic switch, Cell Reports, 2016
  18. 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
  19. 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
  20. Sivanand, S. Rhoades, Q. Jiang, J.V. Lee, J. Benci, J. Zhang, S. Yuan, S. Zhao, A. Carrer, M.J. Bennett, A.J. Minn, A.M. Weljie, R.A. Greenberg, and K.E. Wellen, Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination, Molecular Cell, 2017
  21. JV Lee, K Kim, CT Berry, P Sen, T Kim, A Carrer, S Trefely, S Zhao, LE Barney, AD Schwartz, S Fernandez, SR Peyton, NW Snyder, SL Berger, BD Freedman, KE Wellen, Acetyl-CoA promotes glioblastoma cell adhesion and migration through Ca2+-NFAT signaling, Genes and Development, 2018
  22. Carrer A, Parris JLD, Trefely S, Campbell SC, Norgard RJ, Egolf SS, Sidoli S, Trizzino M, Sivanand S, Sela Y, Blair IA, Garcia BA, Nathaniel W. Snyder, Stanger BZ and Kathryn E. Wellen, ACLY-dependent metabolic and epigenetic reprogramming promotes pancreatic tumorigenesis, Cancer Discov, 2019
  23. Sidoli S, Trefely S, Carrer A*, Integrated Analysis of Acetyl-CoA and Histone Modification via Mass Spectrometry to Investigate Metabolically Driven Acetylation, Methods Mol Biol, 2019
  24. 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
  25. Paoli C & Carrer A*, Organotypic culture of acinar cells for the study of pancreatic carcinogenesis, Cancers, 2020

   

   

  

  ALESSANDRO CARRER

  • Junior 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

  • iCARE-2
  • MFAG