Ovarian cancer devastates more than 20,000 women in the United States every year, due in part to its tendency to evade detection and present after metastatic spread. A key element to slowing metastasis is understanding the mechanisms of how tumor cells invade tissues.
In a paper published Aug. 3, 2021, in the journal APL Bioengineering, by AIP Publishing, University of Wisconsin-Madison engineers explain how microscopic defects in how healthy cells line up can alter how easily ovarian cancer cells invade tissue. Using an experimental model, where the cellular makeup mimics the lining of the abdominal cavity, the group found disruptions in the normal cellular layout, called topological defects, affect the rate of tumor cell invasion.
“My lab is very interested in identifying ways to slow metastasis. This study is exciting, because it demonstrates a unique role for organization of nontumor cells to either aid or slow that process,” says Pamela Kreeger, professor of biomedical engineering and one of the paper’s senior authors. “Identifying factors that regulate this organization could help us to achieve our goal.”
Topological defects are well known to the world of physics, ranging from quantum field theory to cosmological phenomena, but are only starting to find use in medicine and biology.
The group’s model consisted of a single layer of healthy cells, called mesothelial cells, the predominant cell type that covers structures inside the abdomen, where ovarian cancer often metastasizes.
“A common way to fill space is a honeycomb-like packing, in which each ‘cell’ would be nearly spherical,” says Jacob Notbohm, the Harvey D. Spangler Assistant Professor of engineering physics and the other senior author on the paper. “But in our case, the mesothelial cells were elongated, making the honeycomb packing not possible.”
Such elongation led to areas of well-ordered cell layers and left other areas with alignment imperfections, causing the topological defects. These flaws in this alignment have been associated with a host of microscopic influences, including altered cell density, motion, and forces.
They seeded ovarian cancer cells on top of the mesothelial cell layer and compared what effect the arrangement of the mesothelial cells had on how the tumor cells passing through this barrier.
The patterns of cell flow were different near the defects, with certain defects causing inward cell flow, toward the center of the defect. At those locations of inward flow, the cancer cells passed through the mesothelial barrier more slowly.
In addition to pursuing the impact of topographical organization in cancer cell metastasis, the group is looking to investigate the cause of topological defects, with the hopes of finding ways to direct cell patterning in uses, such as tissue engineering.
Jun (Jay) Zhang, a PhD student in biophysics in the Notbohm Research Group, was first author on the paper. Ning Yang, an assistant scientist in the Kreeger Lab, was also a coauthor.