LA JOLLA, CA (US), September 2018 —A team at the Salk Institute has identified a master switch that appears to control the dynamic behavior of tumor cells that makes some aggressive cancers so difficult to treat. The gene Sox10 directly controls the growth and invasion of a significant fraction of hard-to-treat triple-negative breast cancers.
Recently, the Salk lab led by Geoffrey Wahl, Ph.D., discovered that aggressive breast cancers return to a flexible, earlier state found in fetal breast tissue. This cellular reprogramming may be the key to cancer's ability to form new cell types, evolve drug resistance and metastasize to other locations in the body.
The new work documenting Sox10's role in this process, which was reported recently in Cancer Cell, represents a major milestone in researchers' understanding of cancer and could open new avenues for diagnosing and treating aggressive breast cancer as well as other types of intractable cancers.
In order to develop from a single cell into a complete organism such as a mouse or human, embryonic and fetal cells have the ability to divide rapidly, move throughout the body and change into multiple different cell types—properties known as "plasticity." But adult cells turn off this plasticity, which, for reasons that aren't fully understood can get reawakened and turn cells cancerous.
In the new study, the Wahl lab began by examining which parts of mouse mammary cells' DNA — which is tightly coiled in a package called chromatin — was uncoiling to make specific genes more accessible. This was the team's first clue to which genes might be active during development.
"In fetal cells, which are the most 'plastic,' we saw that binding sites for Sox10 were very open and accessible compared to healthy adult cells, which are mostly inflexible and the chromatin is very closed," said Chi-Yeh Chung, Ph.D., a Salk research associate and the paper's co-first author.
The researchers caution that strategies to block Sox10 will require further development and will have to be tested for safety to determine if they impact normal cellular functions. However, the fact that Sox10 regulates many genes potentially linked to aggressive breast cancer offers the potential to target one or more of them as the basis for developing "personalized" therapies for metastatic breast cancer.
During breast cancer, some cancer cells will leave the tumor to invade into nearby tissues. In this new paper, Salk scientists find that the gene Sox10 is important in activating this local invasion.
Left panel: Significant numbers of invasive cancer cells with Sox10 (red) in them can be found outside of the tumor (green cells, outlined).
Right panel shows the invasive cells' proximity to blood vessels (white). Images courtesy of the Salk Institute.