If these tiny tumor cells could be kept dormant — or quiescent — brain metastasis could be prevented, Ghajar said. But it’s first necessary to achieve a better understanding of the mechanisms of dormancy in the brain, which are currently unknown.
Keep ‘em sleeping
With this new award, Ghajar and his team, led by postdoctoral researcher and neuroscientist Dr. Jinxiang (David) Dai, hope to define and characterize the brain’s microenvironmental drivers — the signals from the surrounding normal cells — that put and keep cancer cells asleep after they’ve disseminated there from a primary tumor in the breast.
Their plan is to follow breast tumor cells upon their arrival to the brain in order to define the cues that make them dormant, and to unravel the consequent signaling that wakes them up.
In previous research, Ghajar’s lab showed that DTCs nestled close to the microvasculature, the tiny blood vessels of the bone marrow, survive chemotherapy because they’re being “protected” by that microenvironment.
This work led to the discovery that certain proteins known as integrins, which among other things help with cell signaling, could be used to interrupt this protective signaling. Clinical trials of integrin inhibition are in the offing.
Now, they hope to figure out how to similarly interrupt the protective process in the brain.
Their previous investigations have shown that dormant DTCs are housed within the brain’s vascular niche, where tiny perivascular “astrocytes” — a type of brain cell — keep them from growing.
“They absolutely contribute to DTC suppression,” Ghajar said. “The question is how.”
Once Ghajar's team has gained a better understanding of the framework for how the brain’s microenvironment drives DTCs into a dormant state, they plan on leveraging that into therapies that keep tiny seeds of brain metastasis asleep indefinitely.
“We’re starting with a blank slate, so we don’t know where this will go,” he said. “But it is logical that we have to understand how our body puts tumor cells to sleep — and the brain uniquely — before we can hope to double-up on this process.
“The goal here is understanding how the brain drives tumor cells into dormancy, and how tumor cells overcome this, to develop prophylactics for brain metastasis prevention.”
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