Scientists at Stanford University have uncovered a novel physical mechanism that breast cancer cells use to break out and become invasive. They observed that in addition to established chemical methods of degrading the basement membrane, cancer cells work as a group to physically deform and tear through the basement membrane barrier.
Their findings are published in Nature Materials in an article titled, “Cell volume expansion and local contractility drive collective invasion of the basement membrane in breast cancer.”
“Breast cancer becomes invasive when carcinoma cells invade through the basement membrane (BM)—a nanoporous layer of matrix that physically separates the primary tumor from the stroma,” the scientists wrote. “Single cells can invade through nanoporous three-dimensional matrices due to protease-mediated degradation or force-mediated widening of pores via invadopodial protrusions. However, how multiple cells collectively invade through the physiological BM, as they do during breast cancer progression, remains unclear. Here we developed a three-dimensional in vitro model of collective invasion of the BM during breast cancer. We show that cells utilize both proteases and forces—but not invadopodia—to breach the BM.”
“When this invasion process has been studied, the focus has typically been on single cells,” said Ovijit Chaudhuri, PhD, an associate professor of mechanical engineering and bioengineering, Stanford University. “But what we know is that the invasion is actually collective in nature, involving groups of cells working together to penetrate through the basement membrane. Our work has elucidated how cells act together to break through the basement membrane, advancing our fundamental understanding of this critical transition in cancer progression.”
Previous research has shown that individual cancer cells can produce enzymes, called proteases, that break down some of the basement membrane, but treatments inhibiting proteases haven’t been able to stop cancer cells from breaking loose.The research team developed a new model to study breast cancer and the basement membrane in three dimensions to determine if other mechanisms were at work.
“What we’re really looking at are the mechanical forces involved, which is a different perspective,” said Julie Chang, who conducted the work as a doctoral student in Chaudhuri’s lab and is one of the lead authors on the paper. “The current paradigm is that cells use chemicals to degrade through the basement membrane, but we show that this physical aspect is just as important.”
The scientists designed a 3D hydrogel that mimics the properties of breast tissue and cultured cellular structures, called acini, that exhibit features of a breast duct and are surrounded by their own basement membrane. They tagged the basement membrane with fluorescent markers so that they could see and measure any deformation as cancerous cells interacted with it. And what they saw surprised them.
The cancer cells trapped within the acini swelled together, causing the basement membrane to stretch like a balloon. This stretching process thinned and weakened the basement membrane, which allowed cancer cells near the membrane to apply additional forces to open holes and escape.
The scientists determined that key findings from their 3D model were consistent with what has been seen in patients with invasive breast cancers. They also consulted with colleagues at the University of Pennsylvania who were able to validate their results with computational modeling, confirming the physical forces involved could theoretically allow cells to break through the basement membrane.
The scientists are investigating how cancerous cells physically interact with the surrounding breast tissue once they break through the basement membrane and diving deeper into understanding the basement membrane itself.
“This global volume expansion mechanism represents a new insight into how the breast tumors become invasive, borne out of the development of a 3D culture model that allowed us to visualize the invasion process,” Chaudhuri said. “It highlights the emergent behaviors arising in groups of cells acting together that enable cancer invasion.”