My Second Scientific Paper: Matrix Protease Activity in Tumor Cell Invasion

The second paper from my undergraduate work at Texas A&M University was recently published in Molecular Cancer. The abstract can be found here, and the pdf of the full paper here. Molecular Cancer is an open access journal, so a subscription is not required to read the paper. It's also an online-only journal that publishes manuscripts immediately upon acceptance, so the version of the paper currently available is not the final (nicely-formatted) version. (Update: this now links to the final version of the paper.)

As with my first paper, which was published in October of this year, I'm once again the fourth author, meaning that this was not my primary project. In this case, I was involved mostly with the earlier stages of the project, performing some of the initial migration experiments. Most of my work in the Davis lab focused on Boyden chamber migration assays, so the methods I developed and optimized for performing these types of experiments and quantifying the results were used in this paper.

I won't summarize all of the results here, but those who are interested in cell motility, the extracellular matrix, or cancer biology should definitely take a look at the paper. I will, however, point out what I believe are the most significant contributions of this particular paper. This paper examines the response of various lines of tumor cells to two lipid growth factors: lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). These two lipids have opposing effects on most lines tested, with LPA increasing cell motility, but S1P decreasing it. Interestingly, there was one exception: HT1080 fibrosarcoma cells. These cells, which are some of the most invasive cancer cells known, actually migrate in response to both lipids. Cancer can be thought of as a progressive loss of a cell's regulatory pathways, and this study indicates that the loss of the S1P anti-motility pathway may contribute to the incredibly invasive phenotype of these cells.

In what I think is its most important contribution, though, this study backs up the fundamental idea that cell migration and cell invasion of a matrix are not two identical processes. Instead, cell invasion involves cell migration in addition to other processes, most notably proteolysis of the extracellular matrix. Basically, for a cell to "migrate" in vivo, it not only has to be mobile, but it also has to chew a path through the matrix. This is backed up in our study by the fact that some cell lines migrated in response to LPA but would not invade into a collagen matrix. These cells were deficient in MT1-MMP, a protease that cleaves collagen. I cannot stress this point enough, because still to this day, some in the field use the terms "migration" and "invasion" interchangeably. Most notably, migration assays (including Boyden chamber assays) are sometimes referred to as "invasion" assays. As our paper shows, though, the two cannot be equated, and if an assay does not require the penetration of a matrix, it does not really measure invasion. This is important, because when cells move in vivo, invasion of a matrix is almost always involved. Migration assays are still very useful, though, because they can be used to isolate and study one particular aspect of cell invasion.

Kevin E. Fisher, Andreia Pop, Wonshill Koh, Nicholas J. Anthis, W. Brian Saunders, and George E. Davis, Tumor cell invasion of collagen matrices requires coordinate lipid agonist-induced G-protein and membrane-type matrix metalloproteinase-1-dependent signaling, Molecular Cancer 5 (2006), 69.