Three Proteins Flip the Tumour Sphere. Blocking Two of Them Flips It Back Toward Chemo-Resistance.
A research article in Nature Communications, announced by the University of Turku on 25 August 2026. Groups at Turku Bioscience Centre and the Gustave Roussy Institute studied mucinous colorectal adenocarcinoma, which accounts for roughly 10 to 15 percent of colorectal cancers and disseminates as compact tumour spheres that seed the peritoneum. Working from patient tumour samples and laboratory-grown spheres, they traced the molecular sequence triggered when a sphere contacts collagen in the surrounding connective tissue, then tested therapeutic antibodies against two of the proteins identified.
- Collagen contact is the trigger. Contact with the structural protein of the stroma sets off a multi-step sequence that raises levels of three proteins in the cancer cells: SorLA, HER2 and HER3.
- Those three proteins flip the sphere’s polarity. Their activity reverts spheres from the inverted state, where mucus coats the outside, to the conventional state, where mucus sits inside, and strengthens integrin adhesion to surrounding tissue. Attachment is the step thought to establish peritoneal metastasis.
- Patient samples matched the laboratory pattern. SorLA, HER2 and HER3 levels were highest in conventional-state spheres and lower in inverted ones, which is the correlative basis for using them to identify patients at elevated risk of peritoneal spread.
- Antibodies against HER2 and HER3 impaired attachment. In laboratory-grown spheres, treatment caused cells to die, inverted the spheres, and reduced their ability to attach to the peritoneum. Agents against both receptors are already marketed in other tumour types.
The therapeutic direction runs against the paper’s own description of the two states. The release characterises the inverted sphere as the dangerous one: its external mucus layer shields the cluster from cytostatic drugs, aids migration and improves tissue invasion. Blocking HER2 and HER3 pushes cells back into exactly that state. The authors report cell death alongside the inversion, so this is not a contradiction, but it is a trade with two sides. An anti-adhesion strategy that reduces peritoneal seeding while shifting surviving cells toward the phenotype described as chemo-resistant needs its combination sequencing worked out before it reaches a protocol. That question is the most useful thing here for anyone running a HER2 or HER3 asset.