At Keio University School of Medicine in Tokyo, researchers led by Professors Shigeki Sekine and Toshiro Sato have upended a fundamental assumption about how small intestinal cancers begin—discovering that tumors can form through a completely different genetic route than scientists have long believed.
For decades, researchers have understood that mutations in the APC gene play a central role in intestinal cancers by disrupting the Wnt pathway, a cellular signaling system that controls how intestinal cells grow, divide, and renew. APC acts as a brake on this pathway, and when it breaks, cells can spiral into cancer. Yet when researchers looked closely at small intestinal tumors, they found a puzzle: while APC mutations appear in about 90% of benign small intestinal adenomas, they show up in fewer than 30% of malignant adenocarcinomas. Something else was clearly at work, but nobody knew what.
Sekine and Sato's team, including Associate Professor Masayuki Fujii and Assistant Professor Naoko Abeto, set out to solve this mystery by examining unusual adenomas from three patients—tumors that were protruding rather than flat, with branched glands and distinctive structural features. Using genetic sequencing, they discovered something entirely unexpected: recurrent deletions in a gene called COPA, which had never before been linked to cancer. Rather than controlling the Wnt pathway directly, COPA encodes a component of the coatomer complex, a cellular machine that shuttles proteins between the Golgi apparatus and the endoplasmic reticulum.
When the team screened a larger group of small intestinal tumors, they found COPA mutations again—and crucially, in cases where APC and other known Wnt pathway genes were completely untouched. This meant COPA represented a genuinely independent path to cancer, not a secondary effect. "Scientists have exhaustively hunted down genes responsible for cancer, so this was a shocking new find," said Dr. Fujii.
To understand how these COPA mutations actually trigger cancer, the researchers grew miniaturized intestinal organoids from patient tumors and introduced COPA mutations into healthy organoids using gene-editing tools. Both approaches revealed the same mechanism: COPA mutations activate the Wnt pathway in an unusual way that bypasses the normal requirement for R-spondin and Noggin, two crucial proteins that typically amplify Wnt signaling. In other words, COPA-mutated cells were hacking the Wnt pathway through a backdoor.
The implications ripple across clinical practice. Small intestinal cancers are rare, accounting for only 3% of all gastrointestinal cancers, and have proven difficult to classify and diagnose compared to far more common colon cancers. This discovery could reshape how doctors categorize intestinal tumors and could inform updates to the WHO classification system that clinicians worldwide rely on to identify tumor types in patients. More importantly, it opens a window onto treatment strategies for the significant subset of patients whose tumors lack APC mutations entirely.
The research, published in Nature Genetics, suggests that small intestinal malignancy unfolds along multiple distinct biological paths—a more complex picture than previously understood. As Sekine and Sato's team continues investigating COPA mutations, they hope their work will eventually lead to better diagnostic tools and targeted therapies for patients whose cancers follow this alternative route, potentially transforming outcomes in a disease that has long resisted simple explanations.