Compression Drives Aggressive Behavior in Liver Cancer Cells

Yale researchers are providing new insights into how physical forces, such as cells being compressed in physically restrictive environments, play key roles in cancer progression.

By analyzing liver cancer cells, the researchers found that these cells have a dense tissue matrix, which causes crowding and significant compression within tumors. This physical stress sparks aggressive cellular behaviors, including drug resistance, invasion, and drastic gene expression changes.

"As solid tumors grow rapidly, they grow against their confined surroundings," said Michael Mak, a member of Yale Cancer Center, associate professor of pharmacological sciences at Stony Brook University, and senior author of the study, which published in Cancer Research, a journal of the American Association for Cancer Research. "This causes tumor cells (and the adjacent tissues) to experience compressive forces, so the cells as they grow squeeze against the confined boundaries and against each other. We aimed to explore how this compression can drive tumor progression."

Liver Cancer Cells Under Mechanical Pressure

"A rapidly growing liver tumor in a stiff fibrotic tissue environment, often associated with liver cancer, can impose significant mechanical pressure on the cancer cells, which we quantitatively demonstrated with a computational model," said Xiangyu Gong, a postdoctoral associate in Mak's lab and the study's first author. "We then set up an in vitro experimental platform, a highly controlled experimental setup outside the body, to systematically investigate how prolonged compression can exacerbate liver cancer."

The researchers used innovative techniques to apply compression, exerting mechanical pressure by applying a weight on top of the tumor cells and using hyperosmotic media - a solution with a higher solute concentration than the cells causing water to move out of the cells - to osmotically compress the cells in order to mimic the conditions cancer cells experience within solid tumors. They discovered that this mechanical stress triggers substantial transcriptional changes, or alterations in the process where DNA is copied into RNAs, which directly impacts gene expression. Notably, there was a depletion of liver-specific markers and an increase in genes linked to the progression of cancer.

Further investigation revealed that compression led to an increase in Rac1 protein activity, which is known to encourage the formation of cellular protrusions, or outward extensions of the cell membrane that facilitate cell migration and invasion. This activity also caused the Yes-associated protein (YAP) to move to the nucleus, ensuring the cells' survival even under intense mechanical stress. Additionally, the study found that compression affects intracellular calcium signaling, causing the cells to develop resistance to apoptosis – the process of programmed cell death.

The results indicate that even short-term exposure to compression can cause cancer cells to become more aggressive, drug resistant, and invasive. Researchers hope their findings will pave the way for innovative cancer treatments that address both the biological and physical factors of cancer growth and evolution.

Understanding the influence of compression on liver cancer cells opens new doors for therapeutic interventions. Our study suggests that targeting the pathways affected by compression, such as inhibiting Rac1 activity or altering calcium signaling, may be effective strategies for killing compression-adapted cancer cells."

Michael Mak, member of Yale Cancer Center, associate professor of pharmacological sciences at Stony Brook University

Other Yale authors include Noriyoshi Ogino, M. Fatima Leite, Dingyao Zhang, Zehua Chen, Ryan Nguyen, Raymond Liu, Emma Kruglov, Kaitlin Flores, Aidan Cabral, Gabriel M. M. Mendes, and Barbara Ehrlich.

This study was supported by the National Institutes of Health and Yale University.