"We thought that more 'stuff' for the cells to get through was going to make it harder, so we expected to see less matrix degradation, but instead we found this interesting effect where cells actually sense the rigidity and degrade more," Weaver said.
The team examined how cells convert a sense of matrix rigidity into intracellular signals, a process called mechanotransduction.
Proteins that generate contractile forces, such as myosin "motors," are important players in mechanotransduction. Weaver and colleagues confirmed that myosin motors are involved in sparking more degradation by invadopodia in response to a rigid matrix, though the motors themselves are not present in the drilling structures.
The investigators also implicated the activities of two signaling proteins called FAK and p130Cas in the rigidity-induced invadopodia activity. These signaling proteins were present in an activated state in the invadopodia, suggesting that they are important players in this response and may represent targets for anti-invasive therapies.
Weaver said that it's exciting to find a cellular mechanism that could explain why denser breast tissue is correlated with more aggressive tumors and a poorer prognosis for patients.
"The idea that tissue rigidity leads to a more aggressive phenotype had been out there for a while," she said, "but it hadn't actually been tied to matrix degradation, which is thought to be important for metastasis and spread of cells through the body."
Because metastasis is often what makes cancers deadly, new leads on how to block it are critical, she added.
|Contact: Dagny Stuart McMillin|
Vanderbilt University Medical Center