On Friday, July 8, Ms. Goyette brilliantly defended her doctoral thesis in front of her supervisor, Dr. Jean-François Côté, on the role of the AXL receptor tyrosine kinase in the metastatic progression of breast cancer.
When we know that one woman in eight will be diagnosed with breast cancer during her lifetime and that even with preventive screening and advances in available treatments, this disease remains fatal, mainly because of complications related to secondary tumors that form in distant organs, i.e. metastases, we realize the importance of advancing our knowledge of these mechanisms.
Overview of the thesis
Metastasis is a major clinical challenge and its progression is still not well understood. The AXL tyrosine kinase receptor is widely expressed in various cancers, where it correlates with reduced survival and metastasis formation, but its exact functions in the metastatic process remain poorly defined. In patients with the HER2+ subtype, AXL correlates with mesenchymal characteristics, reduced survival and the presence of metastases. In a preclinical model of HER2+ breast cancer, AXL is required for metastatic progression without affecting primary tumor growth. For this process, AXL circumvents the need for its ligand GAS6 by cooperating with HER2 to promote cell invasion. Thus, the pharmacological inhibition of AXL reduces the metastatic burden. This work therefore identifies AXL as a potential antimetastatic target that can be used in co-therapy with a HER2 inhibitor for the treatment of HER2+ breast cancers. Moreover, the interaction of cancer cells with their environment is essential for tumor progression. Deletion of AXL in cancer cells promotes an anti-tumorigenic microenvironment and reduces metastasis by altering the hypoxic response, showing a novel role for AXL in HIF-1 expression. Thus, AXL inhibition generates an ideal setting for immunotherapy where the combination of AXL inhibition and an anti-PD-1 reduces tumor growth and metastatic burden. These results then suggest that AXL may be an interesting target to modulate the tumor microenvironment by improving immunotherapy and reducing metastatic progression. In conclusion, this thesis provides knowledge on the different roles of AXL in the metastatic progression of breast cancer. These discoveries then led to the study of treatment opportunities including the combination of anti-AXL treatment with other known treatments such as HER2 inhibition or immunotherapy. Thus, the studies conducted in this thesis position AXL as a promising target to increase the survival and quality of life of patients with metastatic breast cancer.
Congratulations, Ms. Goyette!
