Dissecting regulation of the CD44-hyaluronan axis in cancer metastasis

Health Research BC is providing match funds for this research project, which is funded by GlycoNet’s Collaborative Team Grant. Additional funding is provided by the Cancer Research Society. 

This BC-based research project is a collaboration between UBC cancer researchers Prof. Simon Wisnovsky (lead-PI), Prof. Pauline Johnson and Prof. Cal Roskelley. The research of all three Principal Investigators focuses on defining ways that cellular carbohydrates can act as drivers of cancer progression. The majority of deaths due to cancer occur as a result of cancer spread (called metastasis). Thus, it is important to identify molecules that drive metastasis, in order to develop targeted therapies to limit cancer spread. Here, we will determine how one widely expressed cell surface molecule, CD44, drives metastasis and we will identify novel cellular factors that regulate this process. To do this, we will use mouse models of melanoma and breast cancer metastasis, where cancer cells spread to the lung. We will use cancer cells expressing particular forms of CD44, or mutated forms of CD44, and test whether the interaction of CD44 with a long sugar molecule (called hyaluronan or HA) promotes metastasis. We will also determine if one variant of CD44, CD44v6, drives melanoma metastasis. We will then use these mouse models to determine at which stage CD44-HA interactions and CD44v6 affect the metastatic process: migration, survival, or growth in the lung. Next, we will use two innovative high throughput screening approaches (siRNA and Crispr-Cas9) to identify genes that regulate CD44 binding to HA and CD44v6 expression in cancer cells. Putative regulatory genes will be validated, then cancer cells with these genes deleted will be tested in our mouse models of metastasis. Our goal is to identify new proteins that regulate CD44 functions and reduce metastasis. These proteins will provide new targets for intervention and the development of novel anti-metastatic therapies to help cancer patients both in BC and internationally.

End of Award Update – April 2024

Results:

In this project, we used advanced genetic techniques to identify genes that drive metastasis in breast cancer. We have uncovered a number of exciting potential targets that could be candidates for the development of anti-metastasis therapeutics.

Impact & Potential Influence:

Our results have significant translational potential, and we are excited to expand our research to validate hit genes from our studies as potential drug targets.

Next steps:

With the foundational data produced with this study, we have applied for funding from the Canadian Cancer Society and are also preparing a CIHR Project Grant application to fund this project long-term. Our goal is to systematically evaluate a set of novel hit genes as regulators of cancer metastasis using preclinical models, with the ultimate long-term goal of developing new therapeutics that can inhibit cancer metastasis.