An image of mouse colon during chronic colitis displays the effects of inflammation, which can lead to lasting changes in the epigenome that promote cancer.
Image Credit: Courtesy of the Buenrostro Lab
Scientific Frontline: Extended "At a Glance" Summary: Epigenetic Priming of Colorectal Cancer
The Core Concept: Chronic intestinal inflammation leaves lasting molecular scars, or epigenetic "memories," on seemingly healed gut tissues, fundamentally priming these healthy-appearing cells for future cancer development.
Key Distinction/Mechanism: Unlike traditional models that attribute tumorigenesis solely to the gradual accumulation of genetic mutations, this discovery highlights a structural "one-two punch" mechanism. Prior bouts of inflammation alter the cell's epigenome by keeping specific cancer-associated DNA sites open and accessible. If a subsequent oncogenic mutation occurs later in life, the cell exploits these pre-opened genomic regions to rapidly activate cancer-driving genes and accelerate tumor growth.
Major Frameworks/Components:
- Multiplexed Single-Cell Profiling: An advanced analytical method developed to simultaneously measure individual cells' transcriptional states (active gene expression), epigenomic states (chromatin accessibility), and clonal histories (cellular family trees).
- Epigenetic Memory Persistence: The biological phenomenon where specific chromatin regions remain physically accessible despite the cessation of active inflammation and the return of normal gene expression.
- Stem Cell Inheritance: The mechanism by which strong epigenetic alterations are passed from intestinal stem cells to their descendant "daughter" cells across multiple generations of cell division, creating entire lineages primed for malignancy.
- The "One-Two Punch" Model: The synergistic requirement of both an initial environmental/epigenetic alteration and a later genetic mutation to rapidly drive cancer progression.
Branch of Science: Epigenetics, Oncology, Genomics, and Gastroenterology.
Future Application: The immediate potential lies in identifying these specific molecular scars in non-invasive human stool samples, acting as highly predictive biomarkers to stratify individuals at high risk for colorectal cancer decades before tumors form. Long-term applications include the development of novel epigenetic therapeutics designed to "erase" these molecular memories and intercept disease progression.
Why It Matters: This research provides a critical biological mechanism to explain the dramatic, unexplained rise of colorectal cancer among younger adults worldwide. It establishes that transient, early-life environmental exposures—such as diet, lifestyle shifts, or toxins during adolescence—can permanently rewrite a cell's epigenetic landscape and drastically alter lifetime cancer risk, independent of inherited genetic variations.
Chronic inflammation can raise a person’s risk of cancer, and a new study reveals key details about how that might happen in the gut and points to better ways to identify and reduce risk.
Scientists at the Broad Institute and Harvard University have revealed in mice that after colitis, or chronic intestinal inflammation, seemingly healed gut tissues may retain the memory of earlier inflammation through molecular “scars” that make it easier for cancer to take hold later on. These memories are encoded as changes in the epigenome that 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.
Appearing in Nature, 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 study senior author Jason Buenrostro, 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.”
Scars in the epigenome
Colorectal cancer has risen dramatically among younger people in recent decades, pointing to shifts in diet, lifestyle, or exposure to toxins that may be increasing risk rather than changes to heritable genetic variation, which can take thousands of years to arise.
“These factors are transient — your diet in adolescence is not your diet now, but it can affect your cancer risk over a lifetime,” said study first author Surya Nagaraja, a postdoctoral researcher in the Buenrostro lab, a pathology fellow at Massachusetts General Hospital, and a member of team PROSPECT.
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.
The researchers developed a method to measure several things at once in individual cells: the transcriptional state, or which genes are being expressed; the epigenomic state, or what parts of the genome are accessible so that genes in those regions can be turned on or off; and the clonal history, which reveals a cell’s family tree.
Even after the inflammation subsided and tissues appeared healed, the team observed that 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 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.
“Team PROSPECT is working to uncover important insights into the rising global incidence of colorectal cancer in younger adults. If validated in humans, these latest findings suggest that chronic inflammation earlier in life could affect a person’s risk of colon cancer decades later. Importantly, the discovery could help us understand who is most at risk and inform new approaches to prevent or intercept the disease at an earlier stage. It is a powerful example of the kinds of breakthroughs Cancer Grand Challenges was designed to achieve,” said David Scott, Director, Cancer Grand Challenges.
Research material: PROSPECT
Funding: Cancer Research UK, the US National Cancer Institute, the Bowelbabe Fund for Cancer Research UK and the French National Cancer Institute.
Published in journal: Nature
Title: Epigenetic memory of colitis promotes tumour growth
Authors: Surya Nagaraja, Lety Ojeda-Miron, Ruochi Zhang, Ena Oreskovic, Conrad Hock, Yan Hu, Daniel Zeve, Karina Sharma, Roni R. Hyman, Qiming Zhang, Andrew Castillo, David T. Breault, Ömer H. Yilmaz, and Jason D. Buenrostro
Source/Credit: Broad Institute | Leah Eisenstadt
Reference Number: ongy032626_02
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