Stopping the Spread: The Fight Against Metastatic Cancer

By Leslie Ogilvie

4 July 2022

Metastatic cancer – cancer that has spread from the initial tumour site to other parts of the body – is a devastating disease that lacks effective therapeutic strategies and thus remains largely incurable. In fact, over 90% of cancer deaths are attributed to metastatic disease.

“Part of the reason that metastatic cancer is so hard to treat is that we don’t yet fully understand the cellular processes that regulate how cancer spreads,” says Dr. Marc Coppolino, a cell biologist in the Department of Molecular and Cellular Biology.

Coppolino, along with his graduate students, Megan Brasher and Genya Gorshtein, recently made an important breakthrough in this area: they discovered a protein interaction that promotes breast cancer cell metastasis.

A critical factor in the progression of advanced cancer is the breakdown of matrix proteins. These proteins surround cells in tissues, providing a structural scaffold that helps hold cells in place. But tumour cells can form special protrusions called “invadopodia” that are able to break down this matrix, allowing cells from the tumour to invade neighbouring tissues and spread within the patient. Coppolino and his research team identified two proteins ⁠—Syntaxin4 and Munc18c⁠— that promote formation of these matrix-degrading invadopodia.

Using human breast tumour cells in a mouse model of invasive breast cancer, Coppolino and colleagues discovered that the interaction of Syntaxin4 and Munc18c promotes a metastatic cascade by breaking down the matrix barrier within the tumour and facilitating tumour cell invasion to neighbouring regions – a hallmark of metastatic cancer. Interestingly, blocking this protein interaction, by disrupting the expression of the gene encoding Syntaxin4, prevented the degradation of the tumour matrix and reduced tumour cell invasion, slowing the growth of the tumour. Further, when the Syntaxin4-Munc18c interaction was blocked, the spread of cancer to the lungs was almost completely eliminated, which led to much higher survival in the mice.

“This provides evidence that in an animal model of breast cancer, this protein interaction is important for the progression of malignancy”, says Coppolino. “Down the road we could consider this as a target for slowing the development of metastasis while other treatments aimed at the primary tumour are employed.”

Coppolino, whose lab is interested in the mechanisms that regulate cell movement in general, says that findings also have significance beyond the study of cancer.  

“This work is intriguing for our understanding of cancer progression, but it’s equally interesting to gain a better understanding of cell movement in both normal context and abnormal situations, which has a much broader impact in terms of understanding the development of other diseases, too.”

To follow up this work, Coppolino and his team are looking into mechanisms that could explain why tumour cells become more invasive when Syntaxin4 and Munc18c interact and whether this interaction is observed in tumour samples from human patients with breast cancer.

With over 5,000 Canadian women dying from breast cancer every year, understanding the molecular mechanisms of metastasis could pave the way to finding more effective strategies to treat this and other deadly cancers.

This research was driven by the enthusiastic and incredibly diligent work of his graduate students and carried out in collaboration with Dr. Shoukat Dedhar and Dr. Shawn Chafe at BC Cancer.

This study was supported by the Cancer Research Society.

Read the full study in the journal Molecular Cancer Research.

Read about other CBS Research Highlights.