A research team from Memorial Sloan Kettering Cancer Center announced on Aug. 5 that they have identified the protein ZFP36L2, also known as ZFP, as a crucial molecular switch linking the gut’s damage-sensing system to cellular identity shifts necessary for tissue repair. The findings, published in Nature, highlight how this mechanism is exploited by colorectal cancer cells to facilitate metastasis.
According to physician-scientist Karuna Ganesh, MD, PhD, senior author of the study, "This is really a critical process that works the same way across many different tissues—allowing cells to detect damage and turn on stem cell renewal programs." Lead author Quingwen "Karen" Jiang, PhD, said, "Our findings suggest that if ZFP can be disrupted in metastatic cancer cells, it could compromise their ability to start new tumors in other parts of the body."
Under normal conditions in the gut, stem cells produce specialized daughter cells for intestinal function. As these mature, ZFP activity decreases and helps lock them into their identities. In response to injury or loss of stem cells due to inflammation or infection, mature epithelial cells can revert back into stem-like states after passing through a stressed phase—an emergency program mediated by signals which ZFP helps terminate by degrading specific messenger RNAs.
The researchers demonstrated that mice lacking ZFP36L2 struggled with gut recovery after induced injury because their cells could not complete reversion back into stem cell states. Colorectal cancer exploits this wound-healing machinery: metastatic tumor cells require rewinding into a stem-like state via shutting down stress responses—a process dependent on functional ZFP36L2.
Experiments using organoids derived from patient liver metastases showed that depletion of ZFP impaired metastatic spread in mice models despite similar primary tumor sizes. Jiang said, "Cancer cells have to rewind back into a stem cell state in order to spread... When ZFP is missing...the cancer cells simply can't establish a foothold in a new organ." However, loss of ZFP within primary tumors led not only to slower growth but also promoted adaptation toward more aggressive neuroendocrine or squamous characteristics associated with treatment resistance.
Ganesh concluded, "For a long time we studied the ways in which cells were changing identities—but this is the first time we've been able to explain the mechanism behind how it happens...once you understand the mechanism you finally have something concrete to aim at." The team is now exploring whether rapid disruption of ZFP could overwhelm metastatic cancer before it adapts and investigating potential clinical applications such as early identification of high-risk patients.
