Blocking ZFP36L2 protein could disrupt colorectal cancer spread, study finds

The cells lining your gut are under constant assault. Food, bacteria, inflammation—the digestive tract is a punishing environment, and the cells that face it are shed and replaced continuously. This renewal depends on a population of stem cells that work tirelessly to replenish what is lost. But the body has built in a fail-safe: if too many stem cells are destroyed by injury or infection, mature cells that have already specialized can revert to a stem cell state and help rebuild the tissue. It is an elegant biological program, one that has evolved to keep us alive.

Colorectal cancer cells have learned to exploit this same program. When tumor cells break free and travel through the bloodstream to seed new tumors in the liver or lungs, they enter a stressed state much like an injured gut. To establish themselves in a new organ, they must do what healthy tissue does during repair: turn off the stress response and rewind into a stem cell–like state so they can begin multiplying. A team at Memorial Sloan Kettering Cancer Center has now identified the molecular switch that makes this possible—a protein called ZFP36L2, or ZFP for short—and their findings, published in Nature on August 5, suggest a new way to stop cancer from spreading.

Under normal conditions, ZFP36L2 acts like a dimmer switch. As intestinal cells mature and specialize, ZFP activity gradually decreases, locking them into their adult identities. When injury strikes and stem cells are depleted, mature cells receive an emergency signal to rewind. But the transition is not immediate. The cells must first pass through a stressed state—a temporary alarm that signals damage and the need for repair. ZFP's job is to turn that alarm off. It grabs onto messenger RNAs carrying the stress signal and moves them to areas of the cell where they can be broken down, clearing the way for cells to complete their journey back to a stem cell state. Without ZFP, the alarm never stops, and the cells remain trapped in stress. Researchers demonstrated this directly: mice engineered to lack ZFP36L2 struggled to recover after induced gut injury. Their cells simply could not complete the transition back to a stem cell state.

The researchers tested whether blocking ZFP could disrupt cancer's ability to spread. They used organoids derived from patient colorectal cancer liver metastases—miniature tumors grown in the laboratory that retain the key characteristics of metastatic cells. When they depleted ZFP in these organoids and placed them into mice, the results were striking: tumors lacking ZFP largely failed to seed metastases in distant organs, even when the primary tumors were the same size or larger than in control mice. The cancer cells could not rewind back into a stem cell state. They could not establish a foothold in a new organ. The mechanism that allows cancer to spread had been broken.

But ZFP presents a puzzle. While blocking it disrupts metastasis, losing ZFP in a primary tumor can actually help cancer resist treatment. In roughly 5 to 10 percent of colorectal cancer patients, ZFP is mutated or deleted entirely. Rather than simply stalling, these tumors make more aggressive adaptations. Cancer cells that cannot rewind into a normal stem cell state do not simply get stuck—they shift into abnormal identities not usually seen in the intestine. They take on the characteristics of neuroendocrine cells or skin cells, both associated with treatment resistance and worse outcomes. The researchers confirmed this in patient tumor samples: tumors carrying ZFP mutations had switched off their normal stem cell identity and switched on these abnormal characteristics. The cancer cells, unable to enter the stem cell state to make new colon cancer cells, became trapped in a stress-response state that pushed them to rapidly adapt. Under this pressure, cells that could switch identities and survive got selected for, making these cancers much harder to treat.

The findings open several potential paths forward. The most direct involves turning cancer's dependence on ZFP against it. Because tumors rely on ZFP to manage the stress of spreading, rapidly disrupting ZFP could overwhelm cancer cells before they have a chance to adapt. The stress response that keeps them alive would become lethal. The researchers are now actively pursuing this direction. The findings may also point toward new ways of identifying which patients are at highest risk of developing treatment resistance. Because ZFP mutations are already detectable through standard tumor sequencing, patients whose cancers carry these mutations could potentially be flagged earlier for closer monitoring. And the implications may extend far beyond the gut. ZFP belongs to a broader family of proteins that appear to play similar roles in other cancers—related proteins are mutated in roughly 10 percent of all solid tumors. For the first time, researchers have been able to explain the mechanism behind how cells change identities. And once you understand the mechanism, you finally have something concrete to aim at.