A study recently published in the journal Nature Cell Biology by researchers at the University of California, San Diego revealed a new molecular mechanism underlying the link between breast tissue stiffness, breast cancer aggressiveness and poor clinical outcome. The study is entitled “Matrix stiffness drives epithelial–mesenchymal transition and tumor metastasis through a TWIST1–G3BP2 mechanotransduction pathway.”

Breast tumors are frequently detected by touch due to the formation of dense clusters of collagen fibers that render the tumor stiffer or harder in comparison with the surrounding tissue. Increased tumor stiffness is known to be linked to tumor progression, spread (metastasis) and poor survival rates.

In order to assess the influence of tissue stiffness in tumor behavior, the research team used a hydrogel system that allowed them to vary the rigidity of 3D cultures of breast cells between a stiffness degree characteristic of normal mammary glands to the higher stiffness degree typical of breast tumors. The team found that under conditions of high stiffness, a protein known as TWIST1 loses its molecular anchor, a protein called G3BP2, and travels from the cytoplasm into the cell’s nucleus. Once in the nucleus, TWIST1 activates genes that allow breast cancer cells to invade the surrounding healthy tissue and to metastasize into other parts of the body.

“We’re finding that cancer cell behavior isn’t driven by just biochemical signals, but also biomechanical signals from the tumor’s physical environment,” said the study’s senior author Dr. Jing Yang in a news release.

Using mouse models of human breast cancer, with or without G3BP2 expression, researchers found that in the absence of G3BP2, malignant cancer cells were more invasive and exhibited a higher extent of metastasis in the lung when compared to tumors expressing G3BP2. The same finding was observed in human breast cancer patient samples, where stiffer tumors correlated with poorer survival and patients with stiffer tumors and reduced G3BP2 expression exhibited even worse survival rates.

The team suggests that collagen organization (reflecting tissue stiffness) and G3BP2 protein levels can both be used as predictors of a poor clinical outcome and disease progression in breast cancer patients.

The researchers concluded that the molecular pathway involving TWIST1-G3BP2 is responsive to the tumor microenvironment leading to cancer cell invasion, metastasis and poorer patient survival.

“Next we want to understand exactly how cells interpret mechanical cues into biological responses,” said one of the study’s lead co-authors Dr. Laurent Fattet. “This cross-talk between a tumor’s biomechanical microenvironment and the inter-workings of individual cancer cells may someday provide new therapeutic strategies to slow cancer’s spread.”