About Dr. Andrew Freywald
Associate Professor, Department of Pathology, Division of Experimental Patholgy
Associate Member, Department of Biochemistry
1992 MSc, Department of Chemical Immunology, Weizmann Institute of Science, Israel
1997 PhD, Department of Molecular Cell Biology, Weizmann Institute of Science, Israel
Approximately 90% of cancer-related mortality is caused by the invasive and metastatic activities of malignant cells, and the work of my research group mostly focuses on the molecular mechanisms that determine cancer invasiveness and metastasis. In particular, our research addresses the role of the Eph/ephrin system. Eph receptors form the largest family of receptor tyrosine kinases and are divided into EphA (EphA1-10) and EphB (EphB1-6) subfamilies. EphA receptors interact mostly with ligands of the ephrin-A group (ephrin-A1-6), while EphBs are activated by ephrin-B ligands (ephrin-B1-3). Although initially identified as Eph ligands, ephrins also function as active receptors and initiate signaling in their host cells. Both Ephs and ephrins control cytoskeleton and integrin activity, which allows them to regulate cell adhesion and migration. Based on their ability to control attachment and migration Ephs and ephrins are expected to play an important role in metastasis, however, their role in this process is only started to be assessed.
Our investigation of the role of ephrin proteins has revealed that one of the ephrins, ephrin-B1 is consistently expressed in paediatric T cell leukaemias (T-ALLs). We have found that ephrin-B1 induces in T-ALL cells repulsive responses and supports their invasiveness. These observations also demonstrated a new mechanism of ephrin-B1 action, relying on Lck-dependent Rac1 co-localisation with its partner, CrkL, in lipid rafts. Since ephrin-B1-activating EphB proteins are ubiquitously expressed, our findings suggest that ephrin-B1 is likely to play an important role in the regulation of malignant T lymphocytes through the control of lipid-raft-associated signaling, repulsion and invasive activity, and, therefore, may represent a novel target for cancer treatment. This part of our work has been recently published in the journal of Molecular Cancer Research (Jiang et al, Mol Cancer Res, 2008, 6). Currently, we are actively working on the mechanism of ephrn-B1 anti-apoptotic action, which, combined with its ability to induce cell repulsion, is likely to protect T-ALL cells from immuno-elimination in T-ALL patients undergoing bone marrow transplantation (Maddigan et al, J Immunol, 2011, 187).
Our other exciting project examines the role of the EphB6 receptor in breast cancer. Here we showed a new role for EphB6 in suppressing breast cancer invasiveness through the interaction with the anti-oncogenic protein, c-Cbl, regulation of cell morphology and initiation of active adhesive responses. We also showed that EphB6 forms complexes with other EphB receptors to change their behavior from pro-invasive into anti-invasive, therefore, acting as a critical molecular switch in the regulation of the metastatic activity of breast cancer (Truitt et al, Cancer Research, 2010, 70). At this stage, we are actively assessing EphB6 receptor potential as a novel target for breast cancer therapy, aiming to block the development of metastatic disease.
All our research projects are funded by the CIHR granting agency.
LAB OPENINGS: e-mail enquiries for Summers Student, Graduate Student and PostDoctoral positions are welcome.