A tumor's surroundings can reprogram its DNA before it spreads.

When cancer spreads to new organs, it enters unfamiliar surroundings. These surroundings include the extracellular matrix, a structural mesh that surrounds cells and sends them physical and chemical cues. Standard lab dishes do not mimic these distinct organs well. To fix this, researchers created hydrogel gels made from real tissues cleared of their cells. They placed colorectal cancer mini-tumors, called organoids, into these different gels. The matrix composition alone reshaped the cells' chromatin accessibilitychromatin accessibilityA measure of which parts of a cell's DNA are loosely packed and available to be read, controlling which genes are active., which controls which genes turn on. In colon gels, the cancer cells stayed stem-like and acted like primary tumors. In liver gels, the cells activated liver-related gene programs steered by a protein called HNF4A. This liver environment made the cancer cells depend on c-MET signaling to survive. Blocking either HNF4A or c-MET stopped organoids from growing in liver matrix.

Why it matters

Metastasis kills most cancer patients, but we don't fully understand why some tumors thrive in new organs. This work shows that the physical scaffold around cells—the matrix—can actively rewrite a cancer cell's epigenetic instructions, making it dependent on signals specific to that organ. That opens the door to treatments that target those organ-specific dependencies before metastases take hold.

Questions answered