A research team at Memorial Sloan Kettering Cancer Center (MSK) has discovered that a protein called ZFP36L2 plays a central role in intestinal damage repair and colorectal cancer metastasis. Published in Nature on August 5, 2026, the study reveals how this protein acts as a molecular switch, directly linking cellular damage perception with identity transformation, and explains how cancer cells utilize this mechanism to establish new tumors in distant organs.

During digestion, intestinal lining cells are continuously damaged and shed, and are constantly replenished by intestinal stem cells. When the number of stem cells decreases significantly due to inflammation, infection, or other reasons, the body activates a backup mechanism: differentiated mature cells can revert to a stem cell state and participate in tissue repair. This process requires cells to first enter a temporary stress state to receive damage signals, and then complete the transformation into stem cells after the signals are turned off.

The research team discovered that the ZFP36L2 protein is a key factor responsible for shutting down this stress signal. This protein helps cells successfully exit the stress state and reverse their transformation into stem cells by capturing messenger RNA carrying alarm signals and guiding them to degradation regions. Genetically modified mice lacking ZFP36L2 showed significantly reduced recovery ability after intestinal injury; their cells were unable to shut down the stress response and therefore could not effectively transform into stem cells.

Colorectal cancer cells utilize the same damage repair process. When tumor cells detach from their primary site and travel through the bloodstream to the liver or lungs, they need to undergo a similar stress state and regain stem cell-like characteristics in the new environment to proliferate and form metastatic lesions. Using organoid models of colorectal cancer patients with liver metastases, the research team found that after removing ZFP36L2, even when the primary tumor was comparable to or larger than the control group, the tumor cells were largely unable to metastasize to distant organs.

However, the role of ZFP36L2 in primary tumors presents a different picture. In approximately 5% to 10% of colorectal cancer patients, this protein is mutated or completely absent. These tumors, while growing more slowly, tend to transform into more aggressive cell types, such as neuroendocrine cells or squamous cell features. Both of these cell types are associated with treatment resistance and poor prognosis. Researchers confirmed in patient tumor samples that tumors carrying ZFP mutations shut down normal stem cell processes while activating these abnormal cellular features.

Lead author Dr. Jiang Qingwen stated that if ZFP function is disrupted in metastatic cancer cells, their ability to form new tumors in other parts of the body may be significantly impaired. Senior author Dr. Karuna Ganesh explained that tumors rely on this stress response mechanism to cope with the stress during the spread process. If ZFP function is rapidly disrupted, instead of allowing the tumor time to adapt slowly, cancer cells may lose their ability to cope with stress and even self-destruct.

From a clinical perspective, this discovery offers several potential avenues for colorectal cancer treatment. Since ZFP mutations can now be detected through standard tumor sequencing, patients carrying these mutations may be identified as high-risk individuals earlier and receive closer monitoring. Meanwhile, intervention strategies targeting ZFP function are being actively explored by the research team.

The study also points out that ZFP belongs to a broader family of RNA-binding proteins, and mutations in related proteins occur in approximately 10% of solid tumors. This suggests that the mechanism may not be limited to colorectal cancer and may have similar functions in other cancer types. Dr. Ganesh stated that the scientific community has long observed the phenomenon of cells changing their identity, but this is the first time that the specific molecular mechanisms behind it have been explained. Once the mechanism is understood, there are clear targets for intervention.