Cell Shape Changes May Lead to Metastasis
A crucial step in the development of skin cancer may result from changes in the genes that control cell shape, reports a team of scientists from The Methodist Hospital Research Institute, the Institute of Cancer Research (London, UK) and Harvard Medical School. Using automated high-content genetic screening and sophisticated computational modeling, the researchers identified more than a dozen genes that influence cell shape. Their work could lead to a better understanding of how cells become metastatic and, eventually, pinpoint new gene therapy targets for cancer treatment.
This study was led by Chris Bakal of the Institute of Cancer Research and Stephen T. C. Wong of the Methodist Hospital Research Institute. The multi-institutional team published its findings in the journal Nature Cell Biology.
The scientists began their study in fruit fly immune cells called hemocytes. Under normal conditions, each hemocyte was found to take on just one of five distinct shapes about 98 percent of the time. In contrast to conventional wisdom, other shapes and "intermediate" forms were rare, suggesting that the switch between shapes is an all-or-nothing event resulting from expression of a specific set of genes. Genetic manipulation of these cells supported that view as well.
Next the group examined human and mouse melanoma cells, which also take on a variety of forms. The researchers identified seven genes that cause cells to take on primarily rounded or elongated forms, depending on which genes were expressed at a given time in the cells. One of these genes, PTEN, had a particularly strong impact. When turned off, virtually all cells became either elongated or large and rounded, two shapes that can help cancerous cells escape confinement, travel blood vessels, and infiltrate healthy tissues. This information about PTEN is new, even though the gene was previously known to scientists as a tumor suppressor.
The researchers note that increasing the frequency of rounded and elongated cells, compared to taking on a larger number of shapes, would give metastatic cells a survival advantage. Metastatic cells have to become rounded to travel through the bloodstream or invade soft tissues such as the brain, but they need to take on an elongated shape to travel through harder tissues such as bone.
This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, “A screen for morphological complexity identifies regulators of switch-like transitions between discrete cell shapes.” An abstract of this paper is available at the journal’s web site.