- Cancer cell biology
- Tumour biology
About Dr. Andrew Freywald
The work of our team focuses on molecular mechanisms that determine tumor aggressiveness. Cancer cells are often controlled by receptor tyrosine kinases and Eph receptors (EphRs) form the largest group within this family. EphRs are presented by EphA (EphA1-10) and EphB (EphB1-6) types, where EphAs 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 EphR ligands, ephrins are expressed on the cell membrane and can also function as active receptors. Both EphRs and ephrins govern a wide range of responses in differentiated cells and in stem cell populations, and are expected to play a central role in controlling tumor behavior.
Our earlier investigation revealed that ephrin-B1 is strongly expressed in childhood T cell acute lymphoblastic leukaemia (T-ALL). Its action in T-ALL relies on the co-localisation with Rac1, and CrkL cytoskeleton regulators in lipid rafts, allowing ephrin-B1 to support T-ALL invasiveness. The Lck kinase is crucial for ephrin-B1 function and its absence blocks ephrin-B1-induced signaling and invasive activity (Jiang et al., Mol Cancer Res, 2008). Our work in T-ALL also shows that EphB3 and EphB6 are likely to support T-ALL immunoevasion by activating the Akt kinase, and inhibiting Fas-triggered apoptotic cell death. Therefore, these receptors may represent promising targets in therapies, relying on T-ALL immunoelimination (Maddigan et al, J Immunol, 2011). Currently, we are actively working on dissecting the mechanism of EphB6-induced anti-apoptotic action, which is likely to protect T-ALL cells from immunoelimination in patients undergoing bone marrow transplantation (Maddigan et al, J Immunol, 2011).
Interestingly, our work with EphB6 reveals that it has different properties in breast cancer (BC), where it blocks invasiveness (Truitt et al., Cancer Res, 2010). EphB6, although being intrinsically kinase-deficient, undergoes phosphorylation, mediated by the EphB4 receptor. Phosphorylated EphB6 interacts with c-Cbl, which allows it to control the Abl kinase and block the invasive response. Despite its role in EphB6 action, EphB4 also acts in EphB6-independent manner to enhance invasion, suggesting that cancer invasiveness is defined by a balance between pro-invasive EphB4 signaling and the anti-invasive action of the EphB6-EphB4 complex. Moreover, we also found that EphB6 makes BC tumors less drug resistant. In agreement, higher EphB6 levels positively correlate with patient survival and EphB6 expression is reduced in ~ 80% of BC tumors. (Paul et al., Oncotarget, 2016; Toosi et al., Oncogene, 2018). Remarkably, we established that EphB6 downregulation helps to target its synthetic lethal partner, the Src kinase, in breast cancer tumors. EphB6 absence specifically improves tumor elimination caused by Src inhibition, suggesting that Src inhibitors currently used in cancer therapy should be applied in a personalised manner, selectively in EphB6-negative cases (Paul et al., Oncotarget, 2016). Currently, we are initiating phase II clinical trial to translate our finding into clinical applications.
In addition to all this, our most recent work indicates that co-stimultion of EphB6 and the Death Receptor 5 (DR5) may help to selectively kill breast cancer cells (El Zawily et al., Oncotarget, 2016). To translate this finding into new treatment approaches, we are working in collaboration with the Biomirex Inc. (MA, USA) on the development of therapeutic bi-specific antibodies that would act through the EphB6 and DR5 co-activation to eradicate breast tumors.
Our research projects are supported by the CIHR, CCSRI, SHRF and CFI granting agencies, and by the CoMRAD grant provided by the College of Medicine, U of S.
LAB OPENINGS: e-mail enquiries for Summers Student, Graduate Student and PostDoctoral positions are welcome. Pathology residents are encouraged to get involved in short-term projects.
(the complete list of our publications can be found on the PubMed Site: https://www.ncbi.nlm.nih.gov/pubmed/?term=Freywald+A.)
- Toosi B., El Zawily A., Truitt L., Shannon M., Allonby O., Babu M., DeCoteau J., Mousseau D., Ali M., Freywald T., Gall A., Vizeacoumar F.S., Kirzinger M., Geyer R., Anderson D., Kim T., Welm A.L., Siegel P.,Vizeacoumar F.J., Kusalik A., and Freywald A. (2018) EPHB6 augments both development and drug sensitivity of triple-negative breast cancer tumours. Oncogene 37, 4073-4093. Funded by CBCF grant # C7003.
- Tan X., Xu A., Zhao T., Zhao Q., Zhang J., Fan C., Deng Y., Freywald A., Genth H., Xiang J. (2018) Simulated microgravity inhibits cell focal adhesions leading to reduced melanoma cell proliferation and metastasis via FAK/RhoA-regulated mTORC1 and AMPK pathways. Sci Rep 8, 3769-3780.
- El Zawily A., McEwen E., Toosi B., Vizeacoumar F.S., Freywald T., Vizeacoumar F.J., Freywald A. (2017) The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment. Sci Rep 7, 14767-14776. Funded by: the Canadian Institutes of Health Research (CIHR) grant # 132192 and Saskatchewan Health Research Foundation (SHRF) grant # 2891. A.E.Z. was supported by SHRF Postdoctoral Fellowship
- Auslander N., Cunningham C.E., Toosi B., McEwen E., Yizhak K., Vizeacoumar F.S., Parameswaran S., Gonen N., Freywald T., Bhanumathy K., Freywald A., Vizeacoumar F.J., Ruppin E. (2017) An integrated computational and experimental study uncovers FUT9 as a metabolic driver of colorectal cancer. Mol Syst Biol 13, 956-972. Funded by: Saskatchewan Health Research Foundation (SHRF) grants: # 2891; 3538.
- El Zawily A., Toosi B., Freywald T., Indukuri V., Vizeacoumar F., Leary S. and Freywald A. (2016) The intrinsically kinase-inactive EPHB6 receptor predisposes cancer cells to DR5-induced apoptosis by promoting mitochondrial fragmentation. Oncotarget 7, 77865-77877. Funded by CIHR grant # RSN 132192, SHRF grant # 2891, CBCF grant # C7003 and by fall-in funds from a CIHR New Investigator Award #244917 to S.L.
- Paul J., Toosi B., Vizeacoumar F.S., Bhanumathy K., Li Y., Gerger C., El Zawily A., Freywald T., Anderson D., Mousseau D., Kanthan R., Zhang Z., Vizeacoumar F.J., Freywald A. (2016) Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment. Oncotarget 7, 50027-50042. Funded by SCA, SHRF grant # 3538, NSERC grant # RGPIN-2014-04110, CIHR grant # RSN 132192, SHRF grant # 2891, and CBCF grant # C7003.
- Cunningham C., Li S., Vizeacoumar F.S., Bhanumathy K., Lee J., Parameswaran S., Furber L., Abuhussein O., Paul J., McDonald M., Templeton S., Shukla H., El Zawily A., Boyd F., Alli N., Mousseau D., Geyer R., Bonham K., Anderson D., Yan J., Yu-Lee L., Weaver B., Uppalapati M., Ruppin E., Sablina A., Freywald A., Vizeacoumar F.J. (2016). Therapeutic relevance of the protein phosphatase 2A in cancer. Oncotarget 7, 61544-61561.
- Zhao T., Tang X., Umeshappa C., Ma H., Gao H., Deng Y., Freywald A., Xiang J. (2016) Simulated Microgravity Promotes Cell Apoptosis Through Suppressing Uev1A/TICAM/TRAF/NF-κB-Regulated Anti-Apoptosis and p53/PCNA- and ATM/ATR-Chk1/2-Controlled DNA-Damage Response Pathways. J Cell Biochem 117, 2138-48.
- Jessulat M., Malty R., Nguyen-Tran D., Deineko V., Aoki H., Vlasblom J., Omidi K., Jin K.. Minic Z., Hooshyar M., Burnside D., Samanfar B., Phanse S., Freywald T., Prasad B., Zhang Z., Vizeacoumar F., Krogan N., Freywald A., Golshani A., Babu M. (2015) Spindle Checkpoint Factors Bub1 and Bub2 Promote DNA Double-Strand Break Repair by Nonhomologous End Joining., Mol Cell Biol 35, 2448-63.
- Allonby O., El Zawily A., Freywald T., Mousseau D., Chlan J., Anderson D., Benmerah A., Sidhu V., Babu M., DeCoteau J., Freywald A. (2014), Ligand stimulation induces clathrin- and Rab5- dependent downregulation of the kinase-dead EphB6 receptor preceded by the disruption of EphB6-Hsp90 interaction., Cell Signal 26, 2645-57. Funded by SHRF.
- Paul J., Templeton S., Baharani A., Freywald A., Vizeacoumar F. (2014) Building high-resolution synthetic lethal networks: a 'Google map' of the cancer cell. Trends Mol Med 20, 704-715.
- Maddigan, A., Truitt, L., Arsenault, R., Freywald T., Allonby O., Dean J., Narendran A., Xiang J., Weng A., Napper S. and Freywald A. (2011) EphB receptors trigger Akt activation and suppress Fas receptor-induced apoptosis in malignant T lymphocytes, J Immunol 187, 5983-94. Funded by CIHR, Funds #: 73726 and COP-107969.
- Truitt L, Freywald A. (2011) Dancing with the dead: Eph receptors and their kinase-null partners. Biochem Cell Biol 89, 115-29. Funded by CIHR, Fund #: 73726.
- Truitt, L., Freywald, T., DeCoteau, J., Sharfe, N. and Freywald A. (2010) The EphB6 receptor co-operates with c-Cbl to regulate the behaviour of breast cancer cells, Cancer Res 70, 1141-53. Funded by CIHR, Fund #: 73726.