Faculty
Oncology Division
Alphabetical list (active faculty):   
George P. Souroullas

George P. Souroullas, PhD

Assistant Professor

Department of Medicine

Oncology Division

Molecular Oncology

Research Interests

  • Epigenetic mechanisms
  • B cell lymphoma
  • Melanoma

Contact

Research

Overview

The Souroullas Lab is studying the role of epigenetic mechanisms during cancer formation, with a specific interest in B cell lymphoma and melanoma.

Recent next generation sequencing studies have identified mutations in many epigenetic factors in multiple cancers. The reversible nature of these proteins presents us with an opportunity in translational medicine. Understanding the phenotypic and molecular consequences of epigenetic dysregulation during carcinogenesis remains a challenge, but it is critical in developing more effective therapeutic strategies. Towards that end, our lab combines the use of genetically engineered mouse models with epigenetic, molecular, biochemical, and pharmacological methods to study how mutations in epigenetic factors promote the development of cancer.

Figure

Epigenetics and Cancer

Epigenetic regulation is a very dynamic process which involves three main components: (1) Writers: These are proteins which catalyze the addition of chemical groups on the DNA or chromatin. (2) Readers: Proteins which recognize these chemical groups, interact with them, interpret them and transmit further downstream signals. (3) Erasers: Proteins that recognize these marks and catalyze their removal. All these processes together regulate fundamental processes of the cell, such as DNA transcription, replication, repair, and thus cell growth and proliferation, which is an essential component during cancer development. The Souroullas lab is particularly interested in the role of the Polycomb Repressive Complex 2 (PRC2) in cancer. PRC2 is an epigenetic writer which establishes the repressive epigenetic mark histone 3 lysine 27 trimethylation (H3K27me3), resulting in silencing of gene expression. The catalytic subunit of the PRC2 complex is EZH2 (Enhancer of Zeste Homolog 2). Initially, EZH2 was thought to be a tumor-suppressor since loss-of-function events were observed in Myelodysplastic syndrome (MDS), Acute Myeloid Leukemia (AML) and T-cell Acute Lymphoblastic Leukemia (T-ALL). However, more recent next-generation sequencing studies have also identified activating point mutations and amplifications of EZH2 in a wide range of cancers (Figure 1), suggesting that EZH2 also functions as an oncogene. Furthermore, mutations within the SET domain of EZH2 (e.g. Tyr 641) appear to behave in a neomorphic manner in B cell lymphomas and melanoma, further complicating the role of EZH2 and our understanding of its role in cancer. These data suggest that the role of EZH2 in cancer is cell type-dependent, however, the underlying oncogenic mechanisms mediated by EZH2 point mutations or other genetic aberrations are not fully elucidated and are critical in understanding its role during malignant transformation.

Figure 1

Figure 1. Genetic aberrations of EZH2 in human cancers

Research Goals

Our lab is interested in exploring the above mechanisms using genetically engineered mouse models in combination with molecular, biochemical, and pharmacological approaches. Overall, our goal, is to explore how epigenetic mechanisms interact under homeostatic conditions, how those interactions are perturbed in cancer, how they interact with other oncogenic events and how we can take advantage of this knowledge to design more effective therapeutic strategies. Current projects in the lab include:

  • Investigation of the underlying molecular mechanisms that result in the neomorphic properties of the EZH2 mutations observed in B cell lymphoma and melanoma,
  • Understand the downstream mechanisms responsible for the oncogenesis and disease pathogenesis in EZH2-mutant lymphoma and melanoma, and
  • Unravel the interplay between the various epigenetic modifications during cancer.

Figure 2

Figure 2. Schematic of the interplay between the various epigenetic machineries in an EZH2Y641F background

If you would like to learn more about our work, please contact us directly and also check out our website at: https://sites.wustl.edu/souroullaslab/