Art Courtesy of Mandy Chen.
When a flourishing garden is overrun with a variety of weeds, each festering in different soil types and conditions, it becomes difficult to eradicate these invasive species. This chaotic scene mirrors the challenges researchers face in studying cancer metastasis, where clusters of cancer cells travel through the bloodstream, often leading to devastating consequences. Just as some weeds develop resistance to herbicides, metastatic tumors exhibit diverse genetic traits that help them evade standard treatments, complicating efforts to manage their spread. For decades, scientists have struggled to replicate the chaotic 3D structure of these cell clusters in the lab, limiting opportunities in metastasis research. Fortunately, a breakthrough is on the horizon, driven by innovative research that draws inspiration from nature.
Many cancers follow a common maturation process: they first begin in a localized area of the body; then, in later stages, parts of the growing tumor, called metastases, break off, spreading throughout the bloodstream to the rest of the body in a process known as metastasis. In most cancers, once these metastases spread, survival rates become grim. Until now, a realistic, accurate representation of the disorderly 3D structure of tumor cells has yet to be efficiently produced and replicated in laboratories.
Typically, analysis of tumor cells in the lab starts with growing cells in 2D sheets—a good enough solution for many applications. However, for studies of metastases in the blood, sheets misrepresent reality. “A 2D sheet of cells does not accurately represent the non-uniform and uneven stacking of cells against one another as what occurs in real-life metastases,” said Michael King, a professor of bioengineering at Rice University. Because the current methods of mimicking these realistic 3D tumors are neither efficient nor cost-effective, much research focused on the behavior of metastases has been restricted. However, a new project within King’s lab headed by graduate student Maria Lopez-Cavestany may have broken this barrier.
In a new study funded by the National Institutes of Health (NIH grant number: CA203991), Lopez-Cavestany used a biomimetic approach: utilizing natural phenomena to engineer biological replicas for human disease (in this case, tumor formation). Coined the superhydrophobic array device (SHArD), Lopez-Cavestany’s cell-growth device executes what is commonly known as the “Lotus Effect”—a crown jewel in the field of bioengineering. Think about the lotus flower: water droplets bead and fall off its waxy surface. SHArD utilizes this “Lotus Effect” by growing tumor cells in small wells on a superhydrophobic zinc oxide-coated wafer, causing the cells to cluster into a 3D structure. Using the water-shedding property of SHArD, Lopez-Cavestany was able to simulate the unorganized 3D structure of a tumor in a process so straightforward that it could be employed for a low cost by any lab with step-by-step instructions.
The motivation for the project was clear: “[A 3D solution] takes more time and costs more, so for high-throughput drug testing, you usually want something that’s cheap and easy to use to get fast results. But we believe that adding 3D models into mainstream research, maybe after the initial 2D testing, could give more reliable results that better predict how clinical trials will turn out,” Lopez-Cavestany said. Integrating efficient 3D models into mainstream research, as Lopez-Cavestany suggests, could prove essential for testing candidate therapeutics to understand the behavior of cancer cells as they bunch up into clumps within the blood.
The road to discovery was not without its challenges. “We used photolithography, which typically handles thinner layers, but we needed three hundred-micron structures,” Lopez-Cavestany said. “The main issue was adhesion; if the resin cooled too quickly after baking, it could snap off the wafer.” However, thanks to collaboration with Vanderbilt and the Oak Ridge National Laboratories, Lopez-Cavestany developed a protocol using thin grids of resin under a thicker layer to achieve proper adhesion. Such a protocol has allowed SHArD to retain its efficient and replicable nature, critical for future usage in metastasis research.
King is understandably optimistic about this work. “Our goal is to understand how cancer cells survive in the bloodstream long enough to form metastases. If we can prevent that, most cancers could become more treatable and survivable. The experiments in Maria’s paper are a significant step toward advancing that research,” King said.
With this work done, Lopez-Cavestany is continuing her research at Cambridge University, and she plans to become a professor. King and Lopez-Cavestany emphasized their excitement for the next generation of researchers based on their positive experience with this work. If research is a true passion, then go for it, they suggest. Many surprises lie in store.