The growth and death of cancer cells in the lab is studied primarily in two-dimensional cell cultures. In a study publishing in the Cell Press journal Developmental Cell on October 14, researchers instead used three-dimensional models to uncover how pressure and mechanical confinement impact cell growth—halting the cells' metastatic behavior and ultimately leading to their death. The findings could lead to the development of new biomarkers to predict which cancers are more likely to spread, or metastasize, and could ultimately lead to new approaches for preventing metastasis.
"Most previous studies have focused on how cancer cells acquire their ability to migrate," says co-corresponding author Liming Sun, who is from the Chinese Academy of Sciences in Shanghai. "Very few have asked what ultimately happens to these cells if they remain under sustained mechanical confinement, the kind of chronic physical stress they encounter within densely packed tumors. This is what motivated our research."
During the development of solid tumors, cancer cells proliferate and migrate within confined spaces while being subjected to progressively increasing pressure. The new study suggests that cells can interpret this abnormal physical environment as a danger signal, which in turn triggers cell death.
The researchers focused on cancer cells at a particular stage of development, known as the mesenchymal-to-amoeboid transition (MAT). This transition is a biological process in which a cell switches from an elongated, adhesive migration style to a polarized, highly deformable migration style. The process allows cancer cells to rapidly adapt to physical barriers or tight spaces in their environment without waiting for slow changes in gene transcription.
"This work uncovered an entirely unexpected mechanism," Sun says. "In these cells, prolonged mechanical confinement is not merely a physical obstacle to cancer cells, but a signal that activates necroptosis." Necroptosis is a type of programmed cell death.
The team found that physical pressure alone could trigger cell death. This finding has implications for developing new treatments because it suggests that combining cancer therapies with approaches to activate necroptosis could help to reinforce the body's own defenses against cancer development and metastasis.
The researchers also say that MLKL—the protein that triggers necroptosis when cells are under physical pressure—could potentially be developed as a biomarker to predict the likelihood of metastasis because tumors containing lower levels of MLKL would be more likely to spread.
The researchers plan to continue studying this molecular mechanism in greater detail, not only to deepen the understanding of necroptosis but also to potentially reveal new opportunities to therapeutically activate MLKL in cancer. They are also investigating how activated MLKL stops metastasis before confining and killing cancer cells.
"The hope is that by using experimental systems that better reflect the physical conditions that cells experience in living tissues, we can learn more about what fundamentally determines whether a cell lives or dies," Sun says.
