Scientists discover the role of tumor stiffness in promoting cancer cell proliferation

According to the World Health Organization, in 2022 alone, over 20 million people will be diagnosed with cancer and almost 10 million will die from it. Although the scope of cancer is vast, the answer to more effective treatments may lie in a microscopic cell.

A paper published by the Lele Lab, led by Texas A&M University graduate students Samere Zade of biomedical engineering and Ting-Ching Wang of chemical engineering, uncovered new details about the mechanism of cancer progression.

The article, published in , examines the impact of mechanical stiffening of the cancer cell environment on the structure and function of the nucleus.

Cancer turned out to be a difficult disease to treat. It is extremely complex and the molecular mechanisms enabling cancer progression are not understood. Our findings shed new light on how stiffening of tumor tissue can promote cancer cell proliferation.”

Dr. Tanmay Lele, associate faculty member in the departments of biomedical engineering and chemical engineering at Texas A&M University

In the article, scientists reveal that when a cell comes into contact with a rigid environment, the nuclear lamina -; scaffolding that helps the nucleus maintain its shape and structure -; it becomes wrinkle-free and taut as the cell spreads across the rigid surface. This spreading causes Yes-associated protein (YAP), a protein that regulates cell proliferation, to move into the nucleus.

This location may result in increased cell proliferation, which may explain the rapid growth of cancer cells in a rigid environment.

“The ability of stiff matrices to influence nuclear tension and regulate YAP localization may help explain how cancers become more aggressive and perhaps even resistant to treatment in stiffened tissues,” Zade said.

These findings build on Lele’s earlier discovery that the cell nucleus behaves like a liquid droplet. In this work, scientists discovered that a protein in the nuclear lamina called lamin A/C helps maintain the surface tension of the nucleus. A recent study found that reducing lamin A/C levels reduces YAP localization, which in turn reduces rapid cell proliferation.

“The protein lamin A/C plays a key role here; its reduction makes cells less sensitive to environmental stiffness, which particularly affects the localization of the key regulatory protein (YAP) in the nucleus,” explained Zade.

While seemingly complex and specialized, Zade and Lele believe the broader implications of their discovery could inform future cancer treatments.

“Uncovering how matrix stiffness drives nuclear changes and regulates key pathways such as YAP signaling opens the door to the development of therapies that target these mechanical pathways,” Zade explained. “Drugs or therapies can be developed that soften the tumor environment by disrupting the physical signals that help cancer cells grow. Lamin A/C and related nuclear mechanics may become targets for cancer therapies.”

In the future, Lele Lab intends to investigate the extent to which its findings apply to patient-derived tumors.

For this work, the Lele Lab was funded by the National Institutes of Health, the Texas Institute for Cancer Prevention and Research, and the National Science Foundation. Funding for this research is managed by the Texas A&M Engineering Experiment Station, the official research agency of Texas A&M Engineering.