Explore the Bardeesy Lab

Research Summary

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 and patient-derived models to define the role of key gene mutations that drive 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 states that lead to cancer initiation and maintenance. These studies are being used to inform improved therapeutic approaches.

Research Projects

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.

Interplay between metabolism and chromatin regulation in pancreatic and biliary cancer

An important area of current focus in our lab is to elucidate the metabolic regulators of pancreatic cancer and biliary cancers, with particular attention paid to factors that subvert normal differentiation pathways and reprogram cancer cell epigenetics. We have linked mutations in LKB1/STK11 and other important genetic alterations to changes in metabolism that ultimately alter epigenetic states. Identifying these pathways has provided insights in mechanisms of cell transformation arising from these mutations and predict novel therapeutic vulnerabilities. In biliary cancer, there are recurrent mutations in the IDH1 and IDH2 genes. Mutant IDH proteins acquire a novel enzymatic activity allowing them to convert alphaketoglutarate (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.

Genetic regulation of metabolic reprogramming in pancreatic cancer

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 pancreatic cancer, 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. Our recent studies demonstrate that distinct metabolic programs are activated in pancreatic cancer depending on which gene mutations are present. 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.

Understanding and targeting FGFR2-driven biliary cancer

Genetic alterations that activate Fibroblast Growth Factor 2 (FGFR2) signaling are common in biliary cancer and predict response to pharmacological inhibition of the FGFR in patients. However, tumor shrinkage is often modest and acquired resistance invariably arises. We are investigating oncogenic mechanisms controlled by FGFR2 in biliary cancer, including direct targets of FGFR2 signaling as well as downstream impact on cellular metabolism and differentiation. Additionally, we are investigating resistance mechanisms and approaches to prevent and overcome resistance.

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 and the use of this system in large-scale genetic and small-molecule screens to systematically define targetable vulnerabilities in molecularly defined subtypes of this cancer.

Research Positions

Postdoctoral Position - Bardeesy Lab

A 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.

To apply, please email a brief cover letter and CV to nelbardeesy@partners.org.

Publications

Selected Publications

Goyal L, Shi L, Liu LY, Fece de la Cruz F, Lennerz JK, Raghavan S, Leschiner I, Elagina L, Siravegna G, Ng RWS, Vu P, Patra KC, Saha SK, Uppot RN, Arellano R, Reyes S, Sagara T, Otsuki S, Nadres B, Shahzade HA, Dey-Guha I, Fetter IJ, Baiev I, Van Seventer EE, Murphy JE, Ferrone CR, Tanabe KK, Deshpande V, Harding JJ, Yaeger R, Kelley RK, Bardelli A, Iafrate AJ, Hahn WC, Benes CH, Ting DT, Hirai H, Getz G, Juric D, Zhu AX, Corcoran RB, Bardeesy N. TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma. Cancer Discov. 2019 Aug;9(8):1064-1079.

Patra KC, Kato Y, Mizukami Y, Widholz S, Boukhali M, Revenco I, Grossman EA, Ji F, Sadreyev RI, Liss AS, Screaton RA, Sakamoto K, Ryan DP, Mino-Kenudson M, Castillo CF, Nomura DK, Haas W, Bardeesy N. Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism. Nat Cell Biol. 2018Jul;20(7):811-822.

Kottakis F, Nicolay BN, Roumane A, Karnik R, Nagle, J Boukhali M, Hayward MC, Li YY, Chen T, Liesa M, Hammerman PS, Wong KK, Hayes DN, Shirihai OS, Dyson, NS, Haas W, Meissner A, Bardeesy N*. LKB1 loss links the serine metabolism to DNA methylation and tumourigenesis. Nature. 2016 Nov 17;539(7629):390-395.

Saha SK,..., Joung JK, Shokat KM, Benes CH*, Bardeesy N*. Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma. Cancer Discov. 2016 Jul;6(7):727-39.

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.

Saha SK, … , Bardeesy N. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature. 2014 Sep 4;513(7516):110-4. doi: 10.1038/nature13441. Epub 2014 Jul 2.

*Co-corresponding  authors


Research Image

Genetic control of expression of the Mitochondrial Fission Factor (MFF) dictates mitochondrial architecture and metabolic phenotypes of cancer cells. The image shows mitochondrial staining (Mitotracker) of cancer cells which express high levels of MFF (left panel) or low levels of MFF (right panel). The MFF-high cancer cells show hyper-fragmented mitochondria compared to the fused mitochondrial network of MFF-low cancers. This differential control of mitochondrial dynamics results in distinct metabolic programs and vulnerabilities.

Our Researchers

Nabeel M. Bardeesy, PhD

Principal Investigator

Group Members

  • Yasmin Hernandez-Barco, MD
  • Lei Shi, PhD
  • Krishna Tummala, PhD
  • Vindhya Vijay, PhD
  • Vajira Weerasekara, PhD
  • Meng-Ju Wu, PhD
  • Qibiao Wu, PhD
  • Yuanli Zhen, PhD
  • Ramzi Adil, BSc*
  • Ines Faraq, BSc**
  • Joshua Merritt BSc*
  • Rayan Foughali, BSc**
* Research technician
** Visiting master’s student