It is well known that chronic inflammation can increase a person’s cancer risk, but the underlying mechanisms remain unknown. Now, a new study reveals, in a mouse model of colitis, gut tissues may retain the memory of earlier inflammation through changes in the epigenome that make it easier for cancer to take hold later on and are handed down from cell to cell through many generations of cell division, with long-lasting effects on gene activity that can later drive tumor growth. More specifically, “colonic stem cells retain an epigenetic memory of inflammation following disease resolution that persists for more than 100 days.”
Published in Nature, in the paper, “Epigenetic memory of colitis promotes tumor growth,” the work suggests a two-hit process over time in which alterations in the genome—an epigenetic change and a cancer mutation—can accelerate tumor growth. It also points to ways to potentially identify and possibly intervene on these cancer-promoting factors with new biomarkers and therapeutics.
“This finding is a great example of how our experiences and exposures affect our future health,” said Jason Buenrostro, PhD, a Broad core member, professor at Harvard University in the department of stem cell and regenerative biology, leader of the Biology of Adversity Project at the Broad, and a co-investigator on the Cancer Grand Challenges team PROSPECT. “We’ve shown that epigenetic changes are the missing piece in how inflammation leads to cancer.”
In the new study, the researchers focused on chronic inflammation, one of the biggest risk factors for cancer across tissues. In an animal model, the researchers triggered inflammation in the gut and then observed changes to cells in the colon. Even after the inflammation subsided and tissues appeared healed, some cells retained a long-lasting epigenetic memory of the exposure, with certain DNA sites remaining open and accessible even as gene expression returned to normal.
When the scientists later introduced a cancer-promoting mutation, the tissues with epigenetic memory developed larger tumors that grew faster than those in tissues without prior inflammation. The tissues did so by activating sets of genes that contributed to cancer growth and were made more accessible—and hence more easily regulated—through memory of inflammation.
The memory of colitis, they say, is characterized by “a cumulative gain of activator protein 1 (AP-1) transcription factor activity, with durable changes to chromatin accessibility.”
The team developed the SHARE-TRACE method to enable simultaneous profiling of gene expression, chromatin accessibility and clonal history in single cells, enabling high-resolution tracking of epigenomic memory. Through this method, the team uncovered that memory of colitis is “propagated cell-intrinsically and inherited through stem cell divisions, with some clones demonstrating stronger memory than others.
The study concludes that this epigenetic memory is the first of a “one-two punch” that can persist for life, allowing a later mutation to kickstart tumor growth. The team discovered that stem cells with the strongest epigenetic memory passed those changes on to their “daughter” cells, creating whole families of cells primed for cancer.
“In the epigenome, we see this long-lived, robust effect, just waiting for its chance to affect gene expression, and we needed to look at the epigenetic layer in order to see these effects,” said Buenrostro.
He added that the group’s findings could lead to a rethinking of how cancer arises. “We all walk around with cancer-related mutations, but we don’t all have cancer. It’s not just the genetic mutation that matters—the cell type and the experiences that cell has will determine disease outcomes.”
The researchers are exploring whether these molecular scars can be spotted in human stool samples to identify individuals at increased risk. These new clues could also open the door to future treatments that target and correct the underlying mechanism.
