Examining mTORC3 and uncovering its role in tumorigenicity
How tumors grow and expand is an imperative area of study in pediatric disease. If we can understand how malignant cells grow and replicate, we can understand how to slow or stop their growth. Our laboratory examines a growth pathway found in different types of tumors: mechanistic target of rapamycin complex 3 (mTORC3). When this pathway is active, it acts as an amplifier that increases tumor growth and replication. By studying mTORC3, we have two main goals: understand how this complex works and identify small molecules that can block its activation to help combat tumor progression in pediatric patients.
The mechanistic target of rapamycin (mTOR) pathway is a key regulator of cell growth, proliferation, and metabolism. mTOR functions as part of multiprotein complexes that serve to regulate different growth-related functions during cell development. Our current research focuses on mTORC3, a signaling complex in cells that arises from the interaction between ETV7—a transcription factor—and mTOR.
We find about fifty percent of all tumors will activate this complex when cells need a boost of synthetic capabilities to replicate themselves. Because of this mTORC3 (TOR) boost, the complex acts as a tumor amplifier and increases tumorigenicity and frequency. While the complex impacts many different types of tumors, our murine models show a marked increase in the frequency of tumors in rhabdomyosarcoma and acute myeloid leukemia (AML).
To inhibit the activation of this complex, our work focuses on how ETV7 and mTOR interact to create mTORC3 and the composition of the complex. In collaboration with the Department of Chemical Biology and Therapeutics (CBT), we work with the two recognizable domains of ETV7 to discover how they bind with mTOR.
By studying the two domains of ETV7—a pointed domain, which is a protein-protein interaction domain, and an ETS domain, which is a DNA-binding domain—we learned some mutations in both the pointed and ETS domains eliminate ETV7’s ability to interact with mTOR. To uncover what this pointed domain and ETS domain bind to in mTOR and how it functions, we examine the active site of TOR, which resides in a deep cleft in the kinase domain of the protein. On the upper and lower edges of this cleft reside sequences to which each of the ETV7 domains bind. The pointed domain of ETV7 binds to an FRB sequence on one side of the TOR cleft, whereas the ETS domain binds to the LBE sequence on the opposite side of the cleft.
Our goal is to discover small molecules that would interfere with the interaction between these two ETV7 domains once they bind to TOR. Inhibiting this interaction would neutralize the assembly of mTORC3, which provides a possible therapeutic target to slow the progression of malignancies in pediatric patients.
Because of the collaborative nature of our research, our laboratory works as a team that functions within a flow of information. We discuss experiments and interact with each other in an environment of open ideas that fosters discussion and teamwork.
Dr. Gerard C. Grosveld is a faculty member and chair of the genetics department at St. Jude Children’s Research Hospital. He received his PhD from the University of Amsterdam and is an Albert and Rosemary Joseph Endowed Chair in genetic research. He is one of the original discoverers of the BCR-ABL fusion gene in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). Throughout his career, he has won several awards for his research in genetics and cancer. At St. Jude, he leads his lab toward genetic discoveries that enhance our understanding of childhood cancer and reveal possible new therapeutic targets for pediatric patients.
A collaborative team of researchers that lead genetic discoveries to advance the understanding of possible therapeutic targets in childhood cancer treatment.
Gerard C. Grosveld, PhD
Chair & Member
Department of Genetics
MS 331, Room D3055D
St. Jude Children's Research Hospital