In 2022 alone, more than 20 million people were diagnosed with cancer and nearly 10 million died from the disease, according to the World Health Organization. While the scope of cancer is vast, the answer to more effective treatments may lie within a tiny cell.
Led by Texas A&M University graduate students Samere Zade of the biomedical engineering department and Ting-Ching Wang of the chemical engineering department, a paper released by the Lele Lab has revealed new details about the mechanism behind cancer progression.
Posted on Nature communicationsthe article explores the effect that the mechanical stiffness of the cancer cell environment can have on the structure and function of the nucleus.
Cancer has proven to be a difficult disease to treat. It is highly complex and the molecular mechanisms that enable tumor progression are not understood. Our findings shed new light on how tumor tissue hardening can promote cancer cell proliferation.”
Dr. Tanmay Lele, joint faculty in the departments of biomedical engineering and chemical engineering, Texas A&M University
In the article, the researchers reveal that when a cell is faced with a rigid environment, the nuclear lamina -? scaffolds that help the nucleus maintain its shape and structure – it becomes wrinkle-free and stretched as the cell spreads out on the rigid surface. This spreading causes yes-associated protein (YAP), the protein that regulates cell proliferation, to move into the nucleus.
This localization may cause increased cell proliferation, which may explain the rapid growth of cancer cells in rigid environments.
“The ability of stiff matrices to affect nuclear tension and regulate YAP localization could help explain how tumors become more aggressive and perhaps even resistant to treatment in stiff tissues,” Zade said.
These findings build on Lele’s earlier discovery that the cell nucleus behaves like a liquid droplet. In this work, the researchers found that a protein in the nuclear lamina called lamin A/C helps maintain the surface tension of the nucleus. In the most recent study, it was found that reducing lamin A/C levels reduces YAP localization, in turn reducing rapid cell proliferation.
“The protein lamin A/C plays a key role here – its reduction made the cells less responsive to environmental stiffness, particularly affecting the localization of a key regulatory protein (YAP) in the nucleus,” explained Zade.
Although seemingly complex and specialized, Zade and Lele believe the broader implications of their discovery may guide future cancer treatments.
“Uncovering how matrix stiffness drives nuclear changes and regulates key pathways, such as YAP signaling, opens the door to developing therapies that target these mechanical pathways,” Zade explained. “Drugs or therapies could be designed to soften the tumor environment by disrupting the natural cues that help cancer cells grow. Lamin A/C and related nuclear engineering could become targets for cancer therapies.”
Moving forward, the Lele lab aims to explore the extent to which its discoveries 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 administered by the Texas A&M Engineering Experiment Station, the official research organization for Texas A&M Engineering.
Source:
Journal Reference:
Wang, T.-C., et al. (2024). Matrix stiffness motions drop like nuclear deformation and A/C voltage-dependent YAP nuclear localization. Nature communications. doi.org/10.1038/s41467-024-54577-4.
