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Creative Minds: A New Way to Look at Cancer

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Bradley Bernstein

Bradley Bernstein

Inside our cells, strands of DNA wrap around spool-like histone proteins to form a DNA-histone complex called chromatin. Bradley Bernstein, a pathologist at Massachusetts General Hospital, Harvard University, and Broad Institute, has always been fascinated by this process. What interests him is the fact that an approximately 6-foot-long strand of DNA can be folded and packed into orderly chromatin structures inside a cell nucleus that’s just 0.0002 inch wide.

Bernstein’s fascination with DNA packaging led to the recent major discovery that, when chromatin misfolds in brain cells, it can activate a gene associated with the cancer glioma [1]. This suggested a new cancer-causing mechanism that does not require specific DNA mutations. Now, with a 2016 NIH Director’s Pioneer Award, Bernstein is taking a closer look at how misfolded and unstable chromatin can drive tumor formation, and what that means for treating cancer.

How DNA folds in a particular cell depends on the pattern of chemical marks on the DNA itself and on associated histones and other DNA-binding proteins—a phenomenon known as epigenetics. Epigenetic differences explain how cells in different parts of the body can activate unique patterns of genes that allow the cells to behave so differently from each other, despite carrying essentially the same DNA sequence.

Epigenetic controls are disrupted in nearly all forms of cancer. In fact, Bernstein suspects the reason some cells may be more prone to becoming cancerous is that, for still undetermined reasons, their DNA is too easily folded and refolded. That makes them epigenetically unstable.

Bernstein proposes that when epigenetic programming becomes too unstable and malleable to change, cells will aberrantly activate genes and assume a variety of physiological states [2]. In some cases, and perhaps even in a random fashion, certain cells will land on an epigenetic configuration that encourages growth and survival, giving them an advantage over other cells. A few of those cells could even land on an epigenetic pattern that unleashes a program of gene expression that produces a malignant and deadly cancer.

To test his ideas, Bernstein will take advantage of newly established technologies that allow him to profile, monitor, and modify epigenetic landscapes within single cells. That’s critical because, while it’s understood that cells within a tumor can differ significantly in how their DNA is folded and epigenetically programmed, the details remain fuzzy.

Bernstein ultimately wants to develop general models to explain how epigenetic aberrations lead to cancer. To begin, his team will focus on examples of cancers already known to involve epigenetic abnormalities, such as glioblastoma, astrocytoma, and other brain and central nervous system tumors.

In another line of inquiry, the team will focus on the loss of chemical marks to histone proteins. Bernstein posits that stresses leading to a loss of such marks may provide another way for cancer cells to become malleable and access alternative developmental programs. In some cases, those altered programs may also make cancer cells more resistant to treatment.

There’s tremendous excitement among cancer researchers that new treatments targeting the epigenome could have a major impact on cancer care. Prioritizing among the growing list of potential drug targets will require a fuller understanding of the epigenetic factors that drive cancer. Thanks to the efforts of Bernstein and many other researchers around the country, we’re on our way.

References:

[1] Insulator dysfunction and oncogene activation in IDH mutant gliomas. Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suvà ML, Bernstein BE. Nature. 2016 Jan 7;529(7584):110-114.

[2] Epigenetic plasticity and the hallmarks of cancer. Flavahan WA, Gaskell E, Bernstein BE. Science. 2017 Jul 21;357(6348).

Links:

Epigenomics Fact Sheet (National Human Genome Research Institute/NIH)

Bernstein Lab (Massachusetts General Hospital, Boston)

Bernstein Project Information (NIH RePORTER)

NIH Director’s Pioneer Award Program (Common Fund)

NIH Support: Common Fund; National Cancer Institute