Wednesday, March 25, 2026<\/p>\n
NIH-funded animal study finds heritable memories of damage persisted in cells months after inflammation ceased.<\/p>\n
In a new study, funded in part by the National Institutes of Health (NIH), researchers have uncovered a molecular mechanism that could explain how chronic gut inflammation may increase the risk of colorectal cancer. By simulating chronic colitis in mice and tracking the colon\u2019s response during inflammation and recovery, scientists demonstrated that these changes increased the activity of a specific group of proteins, AP-1 transcription factors, and promoted tumor growth.<\/p>\n
The link between inflammation and cancer is well established, but the underlying mechanisms have\u00a0remained\u00a0unclear.\u00a0<\/p>\n
\u201cBy\u00a0spelling out\u00a0how repeated cycles of injury in the gut may\u00a0influence\u00a0colorectal cancer risk, the authors have potentially opened avenues toward much-needed methods\u00a0of\u00a0early evaluation and therapy for a condition that is of increasing\u00a0concern,\u201d\u00a0said\u00a0Anthony\u00a0Letai, M.D., Ph.D.,\u00a0director of NIH\u2019s National Cancer Institute (NCI).\u00a0\u00a0<\/p>\n
The authors, based at the Broad Institute of MIT and Harvard, analyzed the animals and organoids derived from their injured tissue, finding that the damage caused\u00a0alterations in stem cells,\u00a0which new cells inherited for more than 100 days after colitis ceased.\u00a0While an individual\u2019s\u00a0DNA\u00a0generally stays\u00a0the same over time,\u00a0the\u00a0collection of chemical annotations to\u00a0their genome\u00a0\u2014 called the\u00a0epigenome<\/a>\u00a0\u2014 is dynamic.\u00a0\u00a0<\/p>\n This epigenetic flexibility\u00a0allows\u00a0cells to\u00a0adapt to\u00a0shifting\u00a0circumstances, such as damaging inflammation,\u00a0by modulating the expression of certain genes, such as those\u00a0associated with\u00a0regeneration.\u00a0These adaptations can persist as memories\u00a0in the epigenome, but recent research suggests that\u00a0they\u00a0can backfire\u00a0in the long run, inadvertently\u00a0increasing cancer risk<\/a>.\u00a0<\/p>\n The researchers closely examined more than 52,000 individual cells\u00a0across\u00a0the animals,\u00a0identifying\u00a0one\u00a0epigenetic change\u00a0that stood out from the rest. The results suggested\u00a0that colitis led to an alteration\u00a0in colonic stem cells\u00a0that increased the activity of AP-1 transcription factors, which\u00a0are known to steer cellular responses to stress. This memory persisted in the epigenomes of cells for more than 100 days after the authors removed colitis-inducing chemicals from the animals.\u00a0\u00a0\u00a0<\/p>\n To better understand how this\u00a0alteration\u00a0was sticking around so long, the researchers\u00a0developed a method to track epigenetic memories as cells divided\u00a0within an organoid model of colitis, built from injured mouse tissue. They confirmed that the memory of AP-1 was heritable, with colonic stem cells passing it down to new cells as they divided.\u00a0\u00a0<\/p>\n They\u00a0next\u00a0sought\u00a0to find out if this enduring effect of chronic inflammation had implications\u00a0for cancer risk.\u00a0To achieve this,\u00a0researchers introduced\u00a0genes capable of\u00a0sparking\u00a0tumor growth into\u00a0mice\u00a0that\u00a0had either recovered from chronic\u00a0colitis\u00a0or were previously healthy.\u00a0The\u00a0authors\u00a0found\u00a0colorectal\u00a0tumor growth to be far more rapid in the\u00a0colitis-recovered animals compared to the\u00a0other group.\u00a0\u00a0<\/p>\n \u201cWe have known\u00a0for some time\u00a0that colitis can accelerate tumor growth after\u00a0cancer\u00a0has already begun, but here we show that the\u00a0effect of chronic inflammation\u00a0on cancer risk remains\u00a0well\u00a0after\u00a0animals have recuperated,\u201d\u00a0said\u00a0Jason Buenrostro, Ph.D.,\u00a0corresponding author\u00a0and\u00a0member of the Broad Institute and professor at Harvard University.\u00a0<\/p>\n The authors\u00a0found that a slew of regenerative activities associated with AP-1 were in overdrive within tumors of recovered animals. When they blocked AP-1 activity, the\u00a0pro-cancer effect of colitis disappeared, suggesting that this group of\u00a0molecules\u00a0may be\u00a0a central player linking\u00a0chronic inflammation\u00a0in the gut to increased colorectal cancer risk.\u00a0\u00a0<\/p>\n Buenrostro and his colleagues\u00a0believe\u00a0that, if this phenomenon plays out similarly in humans, then tests for these epigenetic memories could potentially inform patients of colorectal cancer risk early on.\u00a0And one day, therapeutics aimed at disrupting\u00a0the\u00a0post-colitis\u00a0activity described in this study\u00a0may\u00a0help stall tumor\u00a0growth.\u00a0\u00a0<\/p>\n This\u00a0study\u00a0is\u00a0part of\u00a0the Cancer Grand Challenges\u00a0team\u00a0PROSPECT<\/a>\u00a0which is\u00a0supported\u00a0by\u00a0NCI grants 1OT2CA297577 and 3OT2CA297577,\u00a0Cancer Research UK, the French National Cancer Institute,\u00a0and the\u00a0Bowelbabe\u00a0Fund for Cancer Research UK.\u00a0This research was\u00a0also\u00a0funded by the National Human Genome Research Institute (NHGRI) through grant UM1HG011986 and by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) through grant P30DK034854.<\/p>\n About the National Cancer Institute (NCI):\u202fNCI leads the National Cancer Program and NIH\u2019s efforts to dramatically reduce the prevalence of cancer and improve the lives of people with cancer. NCI supports a wide range of cancer research and training extramurally through grants and contracts. NCI\u2019s intramural research program conducts innovative, transdisciplinary basic, translational, clinical, and epidemiological research on the causes of cancer, avenues for prevention, risk prediction, early detection, and treatment, including research at the NIH Clinical Center\u2014the world\u2019s largest research hospital. For more information about cancer, please visit the NCI website at\u202fhttps:\/\/www.cancer.gov<\/a>.<\/p>\n About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov<\/a>.<\/p>\n NIH\u2026Turning Discovery Into Health\u00ae<\/p>\n Reference<\/p>\n