Researchers find mechanism that helps aggressive colorectal cancer spread

Scientists in Finland and France identified a molecular switch that helps mucinous colorectal cancer flip between two tumor states as it spreads to the abdominal cavity. The finding could help flag patients at higher risk of peritoneal metastasis and point to new treatment approaches.

Why it matters: - The discovery could help identify colorectal cancer patients most likely to develop metastases in the abdominal cavity. - The mechanism may also open a path to treatments that slow or block spread in aggressive cancers. - The work is especially relevant for mucinous colorectal adenocarcinoma, which accounts for about 10% to 15% of colorectal cancers and is linked to poor prognosis.

What happened: - Researchers from the University of Turku in Finland and Gustave Roussy Institute in France identified a molecular mechanism that controls whether aggressive colorectal cancer cells spread as conventional or inverted tumor spheres. - The study was published in Nature Communications. - The team focused on mucinous colorectal adenocarcinoma, a form of colorectal cancer that is more common in young adults and women. - The cancer often spreads as small, compact clusters of cells that migrate to the abdominal cavity and metastasize on the peritoneum.

The details: - In the inverted state, tumor spheres secrete a mucus layer onto their surface. - In the conventional state, mucus stays inside the cell cluster. - Academy Professor Johanna Ivaska said the mucus layer protects the tumor, reduces the effectiveness of cytostatic drugs, helps cells move into the abdominal cavity, and makes the cells more resistant to chemotherapy. - Some tumor spheres revert to the conventional state after reaching the peritoneum, then attach firmly to surrounding tissue. - Until now, researchers had not known what caused that reversal. - The team studied patient tumor samples and traced a molecular chain reaction triggered when tumor spheres come into contact with collagen in the connective tissue around the tumor. - That sequence raises levels of three proteins: SorLA, HER2 and HER3. - The protein increase reverts tumor cells to the conventional state and strengthens adhesion receptors called integrins. - Patient samples matched the lab results. - SorLA, HER2 and HER3 levels were highest in conventional tumor spheres and lower in inverted ones. - Therapeutic antibodies against HER2 and HER3 already exist for other cancers. - Doctoral Researcher Meri Pelkonen said laboratory-treated tumor spheres began to die, became inverted, and attached less effectively to the peritoneum after antibody treatment. - The team said the results suggest a possible way to slow cancer spread, but more research and clinical trials are still needed. - The research was funded by the Cancer Foundation Finland, Research Council of Finland, Sigrid Jusélius Foundation and EU Horizon 2020.

Between the lines: - The biology helps explain why some aggressive colorectal cancers are especially hard to treat once they seed the abdominal cavity. - The work also strengthens interest in mucus-producing and inversion-based tumor behavior as a broader cancer pathway, not just a colorectal one. - Rising colorectal cancer rates in younger adults make the finding more timely, especially because mucinous colorectal adenocarcinoma is more common in younger patients than other colorectal cancer types.

What's next: - Researchers will need clinical trials to test whether HER2- and HER3-targeted antibodies can slow peritoneal spread in patients. - The mechanism may eventually help clinicians identify patients whose tumors are most likely to metastasize to the abdominal cavity. - Future research may also determine whether the same inversion process drives spread in other aggressive cancers.

The bottom line: - A newly identified protein chain reaction may explain how aggressive colorectal cancer spreads and could point to both a risk marker and a treatment target.