Scientists at the University of Pennsylvania and The Wistar Institute have studied the physical feedback mechanisms between cancer cells and their environment and described how this interplay allows the migration and invasion of tumor cells. Results suggest that targeting the stiffness of the matrix that surrounds the tumor could potentially be used as a therapeutic strategy to prevent metastasis.

In order for cancer to spread, malignant cells must break away from a tumor and through the tough netting of extracellular matrix that surrounds it. To fit through the holes in this net, those cancerous cells must elongate into a torpedo–like shape. The new results, based on a computational model, show that the physical forces exerted between tumor cells and the extracellular matrix, or ECM, are enough to drive this shape change. Those forces converge on an optimal stiffness that allows cancer cells to spread, so that the key factor of this interplay is finding a “sweet spot” in the stiffness of the ECM.

The study, published in the journal Proceedings of the National Academy of Sciences, was led by Vivek Shenoy, PhD, professor in the Department of Materials Science and Engineering in Penn’s School of Engineering and Applied Science and Ashani Weeraratna, PhD, Ira Brind Associate Professor and program leader of the Tumor Microenvironment and Metastasis Program at Wistar.

The research, which is the first quantitative analysis of the shapes of cancer cells as they invade from the tumor, shows that the mechanical factors alone can lead to the change in phenotype in cancer cells.

After the Penn team modeled the interactions in computer simulations, researchers at The Wistar Institute conducted matching experiments to see if the results held up.

“We used melanoma spheroids embedded in a collagen matrix as a 3–D model to recapitulate in vitro what happens in the body when tumor cells leave the primary tumor to invade other tissues,” said Weeraratna. “Our observations perfectly matched and complemented the computer model created by Dr. Shenoy and his team. This study reaffirms, from a mechanobiology standpoint, the crucial role of tumor microenvironment in orchestrating the fate of cancer cells and dictating prognosis and response to therapy.”

“The cells in a tumor are sticky,” said Shenoy. “Without the collagen fibers of the ECM pulling on those cells, you can’t break that cell–cell adhesion. But if the ECM is too stiff, the pores in the matrix become too narrow and the cells can’t escape. The takeaway is that if you look at what’s going on outside the tumor, you could make a prognosis of whether it will spread.”