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Researchers at the Salk Institute has identified a master switch that controls 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 Professor Geoffrey Wahl 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.
Two things that make triple-negative breast cancers so hard to treat are their heterogeneity-they have many different cell types within a single tumor and their ability to move around and colonize new areas, the process of metastasis-imprecision in precision medicine, in the sense that we might target one type of cell, but there are other cells within the tumor that can change to become drug resistant.
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 adults cells turn off this plasticity, which can get reawakened and turn cells cancerous. The embryo will supercharge certain cells to rapidly start critical developmental processes that spawn the growths of new tissues, but it’s very important that these cells get shut off when the body no longer needs this to occur.
In the new study, researchers 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. The chromatin analysis revealed that in both fetal cells and a subpopulation of breast tumor cells, the same areas of the genome were becoming accessible — areas where a master gene regulator called Sox10 is known to bind to DNA to initiate a variety of developmental processes.
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. Sox10 actually bound to genes in the open regions to activate them, thereby directly regulating genes responsible for cell type, mobility and other features relevant to breast cancer’s ability to evolve and metastasize. Breast cancer cells with high levels of Sox10 changed to become much more primitive and acquired the ability to move.
The results were so dramatic that the team repeated the experiment with a technique to keep Sox10 from binding to those genes. This time, without access to Sox10, none of the breast cells that had been programmed to turn cancerous were now able to form tumors.