2 min readResearch Reveals Breast Tumour Stiffness and Metastasis Risk Linked By Molecule’s Movement

San Diego, CA — Researchers at the University of California, San Diego School of Medicine and Moores Cancer Center have discovered a molecular mechanism that connects breast tissue stiffness to tumour metastasis and poor prognosis. The study, published April 20 in Nature Cell Biology, may inspire new approaches to predicting patient outcomes and halting tumour metastasis.

“We’re finding that cancer cell behaviour isn’t driven by just biochemical signals, but also biomechanical signals from the tumour’s physical environment,” said senior author Dr. Jing Yang, associate professor of pharmacology and paediatrics.

In breast cancer, dense clusters of collagen fibres makes the tumour feel stiffer than surrounding tissue. That’s why breast tumours are most often detected by touch — they feel harder than normal breast tissue. But it’s also known that increased tumour stiffness correlates with tumour progression and metastasis, as well as poor survival.

To determine how tissue stiffness influences tumour behaviour, the team of cancer biologists and bioengineers used a hydrogel system to vary the rigidity on 3D cultures of breast cells from that typically experienced by normal mammary glands to the high stiffness characteristic of breast tumours. They discovered that high stiffness causes a protein called TWIST1 to lose its molecular anchor and move into the cell’s nucleus. In the nucleus, TWIST1 activates genes that enable breast cancer cells to invade surrounding tissue and metastasize to other places in the body.

The researchers also compared mouse models of human breast cancer with and without TWIST1’s anchor, a protein called G3BP2. Without G3BP2, tumours were more invasive and developed more metastases in the lung, compared to tumours with G3BP2.

The same mechanism plays out in human breast cancers, too, the researchers found. Analysis of human breast cancer patient samples showed that patients with stiffer tumours (meaning tumours with more organized collagen structures) did not survive as long as patients with more compliant tumours with disorganized collagen. Patients with both low G3BP2 and stiffer tumours had even shorter survival times. The correlations were so clear the team could use these factors — G3BP2 protein levels and collagen organization — to predict patient outcome.

“Next we want to understand exactly how cells interpret mechanical cues into biological responses,” said Dr. Laurent Fattet, a postdoctoral researcher in Yang’s lab who led the study, along with former graduate student Spencer Wei. “This cross-talk between a tumour’s biomechanical microenvironment and the inter-workings of individual cancer cells may someday provide new therapeutic strategies to slow cancer’s spread.”

Article adapted from a University of California – San Diego news release.

Publication: Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Spencer C. Wei et al. Nature Cell Biology (2015): Click here to view.


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