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The Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research
Center for Cancer Research
Nabeel M. Bardeesy, PhDAssociate Professor of MedicineHarvard Medical School
Assistant GeneticistCenter for Cancer Research
Pancreatic cancer and biliary cancer are among the most lethal types of human cancers. The Bardeesy laboratory has developed a series of genetically engineered mouse models to define the role of key gene mutations in driving these cancer types. Current projects focus on defining roles for cancer genes in controlling the way cells modulate their growth and utilize energy in response to available nutrients, and on identifying epigenetic regulators responsible for changes in cellular differentiation state that lead to cancer initiation and maintenance.
Nabeel M. Bardeesy, PhDPrincipal Investigator
The Bardeesy lab focuses on deﬁning the pathways driving the pathogenesis of pancreatic and biliary cancers. Our lab has developed a series of genetically engineered mouse models that has elucidated the functional interactions of major gene mutations associated with these diseases in humans. Speciﬁcally, we have characterized the roles of key cancer genes in the control of cellular differentiation states and in metabolic regulation.
Epigenetic drivers of pancreatic and biliary cancer
An important area of current focus in our lab is to elucidate the epigenetic regulators of pancreatic cancer and biliary cancers, with particular attention paid to factors that subvert normal differentiation pathways and that reprogram cancer cell metabolism. As part of these efforts, we deﬁned the tumorigenic role of a number of chromatin-modifying enzymes that are deregulated in pancreatic cancer progression, KDM2B. This histone demethylase is a major regulator both of polycomb repressor complexes that override cancer cell differentiation states and of a distinct program controlling metabolic homeostasis. In biliary cancer, there are recurrent mutations in the IDH1 and IDH2 genes. Mutant IDH proteins in IHCC and other malignancies acquire a novel enzymatic activity allowing them to convert alpha-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, including the JmjC family histone demethylases. We are focusing on how IDH mutations affect epigenetic programs and regulation of cellular identity in the liver.
Targeting master regulators of metabolic reprogramming in PDAC
In order to couple rapid growth with available nutrients, cancers employ profoundly altered networks of biosynthetic and catabolic pathways. This requirement for metabolic reprogramming is particularly acute in PDAC, which is characterized by hypoxia and limited nutrient availability, and activates anti-oxidant gene expression and autophagy (cellular self-catabolism) as necessary adaptive metabolic changes. While these pathways offer attractive new therapeutic targets, the underlying mechanisms driving altered PDAC metabolism are unclear. We have focused on identifying master transcriptional regulators that broadly orchestrate metabolic reprogramming in PDAC.
Mouse models of biliary cancer
Recent genetic studies have identiﬁed multiple recurrent mutations in biliary cancers and have indicated considerable genetic heterogeneity between individual tumors. A key limitation in the ﬁeld includes a paucity of experimental systems with which to deﬁne the contributions of the lesions to biliary cancer progression. We have established a series of genetically engineered mouse models that incorporate combinations of the major mutations found in the human disease. In addition, our ongoing efforts include the development of a human biliary cancer cell line bank for the use of genetic and small-molecule screening in genetically deﬁned subtypes of this cancer.
Control of liver progenitor cells and biliary cancer development
The Hippo pathway is a conserved regulator of organ size. Our lab has shown that this pathway is central for controlling the quiescence of liver progenitor cells, and that its loss leads to massive liver overgrowth and development of both major types of liver cancer (hepatocellular carcinoma and cholangiocarcinoma). The lab is studying the circuitry of the Hippo pathway in liver progenitor cells and the key mediators of tumorigenesis downstream of this pathway.
Postdoctoral Position - Bardeesy LabA Postdoctoral Research Fellow position is available to study molecular pathways in the pathogenesis of pancreatic and liver cancer, focusing regulators of cell metabolism and epigenetics. The candidate is expected to have a PhD in the biological sciences, and be highly motivated with expertise in basic molecular biology and biochemical techniques. The Fellow will have simultaneous academic appointments at the Massachusetts General Hospital and Harvard Medical School. Studies will involve the use of a number of genetic and biochemical approaches, including genetically engineered mouse models, primary epithelial cell systems, genome-wide analyses, and in vitro genetic screens to study the interplay of epigenetics and metabolism governing cancer initiation and progression. The position provides a rich intellectual environment within a group of young investigators at the MGH Cancer Center and Center for Regenerative Medicine, with full integration into the large research communities of the Massachusetts General Hospital and Harvard.Please email a brief cover letter and CV to:Nabeel Bardeesy, PhDMassachusetts General Hospital Cancer CenterHarvard Medical SchoolCPZN 4216185 Cambridge St.Boston, MA firstname.lastname@example.org
View a list of publications by researchers at the Bardeesy Laboratory.
Perera RM, Bardeesy N. Pancreatic Cancer Metabolism - Breaking it down to build it back up. Cancer Discovery 2015 (in press).
Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant, J, Boukhali M, Lengrand J, Deshpande V, Selig MK, Ferrone CR, Settleman J, Stephanopoulos G, Dyson NJ, Zoncu R, Ramaswamy S, Haas W, Bardeesy N*. Transcriptional control of the autophagy-lysosome system drives amino acid metabolism in pancreatic cancer. Nature 2015 July 13.
Fitamant J, Kottakis F, Benhamouche S, Tian H, Chuvin N, Parachoniak CA, Nagle J, Perera RM, Deshpande V, Zhu AX, Lai A, Min B, Hoshida Y, Avruch J, Sia D, Camprecios G, McClatchey AI, Llovet JM, Morrissey D, Raj L, Bardeesy N*. YAP inhibition restores hepatocyte differentiation in advanced HCC leading to tumor regression. Cell Rep. 2015 Mar 10. pii: S2211-1247(15)00173-4.
Saha S, Parachoniak C, Ghanta KS, Fitamant J, Ross K, Najem MS, Gurumurthy S, Akbay EA, Sia D, Cornella H, Miltiadous O, Walesky C, Deshpande V, Zhu AX, Hezel AF, Yen K, Straley K, Travins J, Gliser C,Ferrone CR, Apte U, Llovet JM, Wong KK, Ramaswamy S, Bardeesy N*. Mutant IDH inhibits HNF4a to block hepatocyte differentiation and pro- mote biliary cancer. Nature. 2014 Sep 4;513 (7516):110-4.
Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014 Sep 11;371(11): 1039-49.
Lee JJ, Perera RM, Wang H, Wu DC, Liu XS, Han S, Fitamant J, Jones PD, Ghanta KS, Kawano S, Nagle JM, Deshpande V, Boucher Y, Kato T, Chen JK, Willmann JK, (Bardeesy N*, Beachy PA)*. Stromal response to Hedgehog signaling restrains pan- creatic cancer progression. Proc Natl Acad Sci U S A. 2014;111(30).
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