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.
- 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)
- 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)