Stromal Cells Take Up More Room in Young Patients' Colon Tumors
A study published Oct. 29 in Nature Medicine offers the most detailed cell-level portrait yet of early-onset colorectal cancer. Researchers from Dana-Farber Cancer Institute, Mass General Brigham and the Broad Institute call it the largest of its kind, a resource meant to guide future work on why the disease behaves more aggressively in younger people.
The team studied surgical specimens from Dana-Farber's gastrointestinal biobank: 189 tumors from patients aged 29 to over 90, including 54 diagnosed before age 50 and 135 diagnosed at 50 or older. First author Caroline Porter of the Broad Institute's Klarman Cell Observatory led the analysis, with senior authors including Dr. Kimmie Ng, director of Dana-Farber's Young-Onset Colorectal Cancer Center, and Dr. Ramnik J. Xavier.
Using single-nucleus RNA sequencing, the researchers measured gene activity in more than 850,000 cancer and neighboring cells, building what they describe as a continuum of colorectal cancer cells across ages rather than a single average snapshot.
The sharpest difference was composition. Among tumors of the most common colorectal cancer subtype, younger patients' tumors held a significantly higher proportion of stromal cells — the connective and supporting cells that form scaffolding around tumors — relative to cancer cells. The pattern held regardless of which side of the colon the tumor arose on, even though young-onset disease often appears on the left side or in the rectum.
That matters because a high stromal share has been linked to chemotherapy resistance in several solid cancers. Stromal cells can shape tumor growth and shield cancer from immune cells and drugs. The authors stress this is a clue, not proof of causation in colorectal cancer.
The team confirmed the pattern in gene-activity data from 564 additional tumors and in computer analysis of stained tissue images from another 712 tumors.
Younger patients also showed higher activity of long non-coding RNAs, molecules that regulate genes without making proteins. Some recurred across cancer cell types, and many are "dark" RNAs whose functions remain largely unknown. The researchers also found gene-activity signals suggesting stronger signaling between cells, plus dozens of differentially expressed genes tied to metastatic potential — a possible explanation for the greater aggressiveness of early-onset disease.
Clinicians quoted in coverage urge people with persistent blood in the stool to call a doctor promptly and not skip colonoscopy out of embarrassment. Earlier diagnosis remains the strongest lever for beating the disease.