Research Centers

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Bardeesy Lab

Research topics include: pancreatic ductal adenocarcinoma

Program Affiliations

Nabeel M. Bardeesy, PhD
Associate Professor of Medicine
Harvard Medical School

Assistant Geneticist
Center for Cancer Research

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 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 master regulators that promote cancer cells to become more primitive and to metastasize. These efforts point to potential new targets for anticancer drugs.

Read the Bardeesy Lab's Annual Report in Full

Nabeel M. Bardeesy, PhD
Principal InvestigatorGroup Members

Postdocs:

  • Julien Fitament, PhD
  • Rushika Perera, PhD
  • Supriya (Shoop) Saha, PhD
  • Filippos Kottakis, PhD
  • Christine Parachoniak, PhD
  • Krushna Patra, PhD

Technicians:

  • Svetlana Stoykova, PhD
  • Julia Nagle
  • Mortada Najem

Reasearch Projects

The Bardeesy lab focuses on defining the pathways driving the pathogenesis of pancreatic cancer and, in more recent efforts, of biliary cancer. Our lab has developed a series of genetically engineered mouse models that have 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.

Lkb1 in regulation of metabolism and stem cell quiescenceThe majority of patients with pancreatic cancer die due to metastasis of the tumor to other organs such as the liver. The process of metastasis involves the loss of cell differentiation (i.e. loss of features of specialized features of mature cells). The KDM2B histone demethylase was found to contribute to overriding differentiation in pancreatic cancer and lead to more aggressive tumor growth. Image shows immunohistochemical staining for KDM2B in pancreatic cancer cells that have metastasized to the liver.
The Lkb1 tumor suppressor encodes a serine-threonine kinase mutationally inactivated in a subset of pancreatic and biliary cancers. The best-defined functions of Lkb1 are to suppress cell growth and to reprogram metabolic pathways in response to energy stress conditions. Our lab recently showed that Lkb1 is critically required for the function of hematopoetic stem cells (HSCs). HSCs are normally largely quiescent but need to be able to rapidly convert to a highly proliferative state. We showed that Lkb1 is essential for maintaining quiescence of these cells and for ensuring appropriate energy utilization. The laboratory is currently defining the contribution of this program to Lkb1-mediated suppression of epithelial cancers.

Transcriptional reprogramming in pancreatic cancer
An important area of current focus in our lab is to elucidate the epigenetic regulators of pancreatic cancer, 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.

Mouse models of biliary cancer
Although biliary cancers are highly aggressive and increasing in incidence, their pathogenesis remains poorly understood. 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 biliary). The lab is studying the circuitry of the Hippo pathway in liver progenitor cells and the key mediators of tumorigenesis downstream of this pathway.

Research Positions at the Bardeesy Laboratory

 

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.

Please email a brief cover letter and CV to:

Nabeel Bardeesy, PhD
Massachusetts General Hospital Cancer Center
Harvard Medical School
CPZN 4216
185 Cambridge St.
Boston, MA 02114

nelbardeesy@partners.org

 

Bardeesy Laboratory

185 Cambridge Street
Boston, MA 02114

Phone: 617-643-2579
Email: nelbardeesy@partners.org

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