Breast cancer spread triggered by a cleaver-wielding protein on cancer cell’s surface 

Scientists from the University of Helsinki and UCSF have exposed a cell pathway that breast tumor cells use to destruct local tissue neighborhood. Cancer cells may use this pathway to free themselves from mammary epithelial tissue architecture, to spread to surrounding tissues.

Cancer rarely kills unless it evolves the ability to spread beyond the tissue in which it developed, to grow into surrounding healthy tissues. An important roadblock for tumor spread is membranous scaffolding, basement membrane, which lines epithelial cell layers in tissues.

Normal epithelial cells and even early-stage tumor cells remain tightly tethered to basement membrane, which segregates healthy and likewise cancerous epithelial cells from surrounding tissues. Breakdown of this barrier allows tumor cells to escape from the tethers of the epithelium, launching a tumor invasion to healthy tissues. 

– If we could delay or prevent a tumor from switching from one that grows in place to one that invades, then that would be a major milestone in cancer treatment, says Professor Zena Werb from UCSF.

In this study, the researchers led by Dr. Juha Klesfröm from the University of Helsinki, identified a molecular pathway in breast tumor cells leading to activation of a protein-cleaving enzyme hepsin on the surface of breast tumor cells. Tumor cells use hepsin to chop basement membrane proteins – to break free from ties and matrix binding them to local neighborhood in their native epithelial tissue.

M.Sc. Johanna Partanen, a graduate student in the research group of Dr. Klefström, designed and led experiments that resulted in the discovery of a biochemical chain of events that is likely to be initiated by many breast tumor cells when they become invasive.

Partanen found that shutdown of gene Lkb1 disturbs development of parts of the mammary gland, including milk-secreting tissue structures. Especially, basement membrane, which normally surrounds tissue structures of the mammary gland was damaged and degraded.

A culprit for basement membrane damages was pinpointed: Lkb1 shutdown disconnected hepsin from normal regulation and the protein mistakenly started to blanket the surface of mammary epithelial cells, causing degradation of the basement membrane.

Researchers found that inactivation of hepsinallowed the basement membrane to recover. These events may take place in many tumors, as the research found that Lkb1 is missing and hepsin is abnormally expressed in 1 out of 4 human breast cancer samples.

Will these findings help us to fight cancer? – Maybe, says Klefström:

– Hepsin is of a type of protein known as a protease and proteases have been successfully targeted in drug development. We found that deactivation of hepsin in the mammary gland organoids prevents formation of a cancerous phenotype. This finding leads us to think that inhibition of Hepsin by drug-like molecules could restrain breast cancer progression. However, we do not know yet if we can cure already formed tumors by blocking hepsin activity.

The study was published in the Proceedings of the National Academy of Sciences (PNAS).

Figure: Scanning electron microscope image shows 2000x magnification of the basement membrane damaged by inactivation of Lkb1-gene. Basement membrane is a matrix of tightly knit protein fibers, hiding mammary epithelial cells under the surface in the figure. On the right side, the basement membrane is intact and the surface is smooth and even. On the left side, the membrane is degraded and damaged. The arrow shows an epithelial cell protruded above the surface of damaged membrane. It is thought that such basement membrane breakdown allows tumor cells to free themselves from epithelial layers and to spread deep in the neighboring tissues.


Text: Päivi Lehtinen
Image: Johanna Partanen

Read more: Some Breast Cancer Spread May Be Triggered By Targetable Protein, Study Shows (UCSF websites)

Press release