Improving responses to cancer treatments by targeting disorderly chromatin

How do cells acclimate to rapidly evolving or completely novel environments? In the case of cancer cells, their existing structural and mutational differences can cause them to become resistant to treatments. And how they change their gene expression in response to chemotherapy is also key to survival. Yet scientists have struggled to identify mechanisms that link this cell diversity with treatment responsiveness—until now.

In a study published in the journal Science Advances, a Northwestern University research team pinpointed the role of chromatin, the DNA, RNA and proteins that make up the chromosome. They reported that the way chromatin is packed in the nucleus can cause diverse DNA transcriptional features among cells and control how they respond to stress.

Cancer cells with disordered packing are more likely to adapt to treatments, they reported. The researchers believe targeting chromatin could inhibit cancer cells' ability to adjust and therefore help boost the response to traditional therapies.

“Genes are like hardware, and chromatin is software,” Vadim Backman, the co-senior author of the study, explained in a statement. “And chromatin packing is the operating system.”

In a separate Science Advances study, Backman and fellow Northwestern bioengineers used mathematical modeling and optical imaging to produce a 3D picture of chromatin folding.

“If the structure of chromatin changes, it can alter the processing of the information stored in the genome, but it does not alter the genes themselves,” Backman said in a statement. “Understanding chromatin folding holds the key to understanding how cells differentiate and how cancer happens.”

For cancer cells, treatments represent stressors. The scientists suspected that chromatin, when it’s chaotically packed, can regulate expression of genes in ways that enable cancer cells to become resistant to treatment. But when the packing is neat and orderly, a cancer cell crumbles in response to outside stressors.

After analyzing gene expression data from The Cancer Genome Atlas, the researchers showed that increased transcriptional malleability in tumor cells—which they linked to chromatin packing scaling behavior—correlates to lower patient survival in advanced colorectal, breast and lung cancers.

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Due to its essential role in controlling gene expression, chromatin has already attracted interest in disease research. A Cambridge, Massachusetts-based biotech called Foghorn Therapeutics was launched in March 2018 with the aim to develop drugs for cancer and other serious diseases based on insights into the chromatin regulatory system.

Backman and colleagues believe targeting chromatin packing could indeed inhibit cancer cells’ ability to adapt, making them vulnerable to treatments.

“We found that transcriptional plasticity and chromatin packing alterations are an important marker, which is indicative of how a cancer patient may respond to anti-cancer therapies, such as chemotherapy,” said Ranya Virk, the study’s co-first author. “The results should inspire new strategies to fight cancer.”