MSK Study Finds Dormant Cancer Cells Alter Shape to Evade Immune Attack

Cancer cells detached from primary tumors can remain dormant for years, avoiding immune detection until conditions favor forming metastatic tumors elsewhere. These metastatic tumors cause as many as 9 in 10 cancer deaths, making their study a key priority in cancer research. New work at Memorial Sloan Kettering Cancer Center (MSK) reveals how these cells lower surface tension by changing shape. Published in Nature Cancer, the findings show that the softer, rounder cancer cells are difficult for immune defenders to grasp.

Led by senior research scientist Zhenghan Wang in the lab of Joan Massagué, the study was conducted in cells and mouse models of lung cancer. “When cancer cells are round, they have much lower surface tension and it’s harder for the immune cells to attack them and pop them like a balloon,” explains Massagué. Using atomic force microscopy, researchers measured how dormant metastatic cells shift from firm, elongated spindle shapes to softer, rounder ones, resembling deflated balloons that resist piercing.

This physical change depends on TGF-beta signaling and the protein gelsolin. Initially, TGF-beta triggers epithelial-to-mesenchymal transition (EMT), transforming stationary epithelial cells into motile, invasive mesenchymal ones that elongate and stiffen. Prolonged TGF-beta exposure, however, boosts gelsolin production. Gelsolin dismantles the cell’s actin fiber scaffolding, reducing stiffness and promoting a rounder shape. Softer cells evade natural killer cells and cytotoxic T cells, which find them harder to latch onto and destroy.

“Our research suggests that if we can stop cancer cells from entering this soft state, or re-stiffen them, we might help the immune system find and clear dormant metastases before they can seed a new tumor,” Wang notes. When researchers blocked TGF-beta, lowered gelsolin, or prevented softening, immune cells eliminated dormant cancer cells more effectively. TGF-beta thus plays a central role in long-term immune evasion during dormancy.

The findings highlight a mechanical defense mechanism in metastasis and suggest treatment possibilities. By targeting shape changes, therapies could expose dormant cells to immune clearance. “We hope that with continuing research into dormant metastasis, we can ultimately prevent metastatic cancer by helping the body eliminate its dormant seeds,” Massagué says.