Scientists have long studied the ins and outs of cancer cells to learn more about the disease, but they're increasingly finding that noncancerous cells near the cancer cells exert a powerful influence over a tumor's trajectory.
"Not all cells in a tumor are cancer cells -- they're not even always the most dominant cell type," said Sylvia Plevritis, PhD, chair of Stanford Medicine's department of biomedical data science. "There are many other cell types that support tumors."
To better capture the whole picture of cells' locations and interactions, Plevritis and a team of researchers have developed something that they call the "colocatome," (pronounced co-locate-ome). Modeled after the nomenclature that describes other classes of molecules and facets of human biology (collective information about genes is called the genome; proteins, the proteome; metabolites, the metabolome, etc.) the colocatome documents the details of malignant cells on their neighbors -- what those cells are and how many of them are present.
"We've been studying cancer cells for so long, but the picture is still incomplete," said Gina Bouchard, PhD, instructor of biomedical data science. "Understanding tumor biology is not only about cancer cells; there's a whole ecosystem that needs to be studied. Cancer cells need help to survive, to resist, to thrive and even sometimes to die."
A study describing the findings was published in Nature Communications last month. Bouchard is the lead author, and Plevritis is the senior author.
Mapping influence
Cancer cells are surprisingly dependent on their surroundings. Depending on the location, type and quantity of noncancerous cells surrounding the tumor, the cells' behavior can change, whether through faster growth, decreased susceptibility to drugs or heightened cell metabolism.
"The questions we're asking are very simple. We want to know who the neighbors are for each cell. Who likes whom? Who doesn't like whom? It's all about which cells tend to be together, and which ones are rarely found together," Bouchard said. Cells that attract each other are described as "colocalizing" while those that seem to repel each other form "anti-colocalizations." Those colocalizations are then linked to the state of the cancer -- aggressive, resistant, susceptible to drugs -- and logged in the colocatome.
The team developed experimental models of lung cancer in the lab, then used artificial intelligence to analyze them, identifying noncancerous cells and how they organized within and around the tumor cells. They then compared the colocalizations with those from patient tumor biopsies. After mapping hundreds of cell configurations, they confirmed that the majority of colocalizations in the primary patient tumors are observed in the experimental models. (That overlap is key, said Bouchard. It means that the models are a valuable and accurate representation of what's happening in someone who has lung cancer.)Past research by Plevritis and others showed strong interactions between fibroblasts and cancer cells, but exactly how fibroblasts interact with cancer cells is unclear. In an experiment, Plevritis showed that lung cancer cells die when doused with a type of anti-tumor drug that stunts cell growth. But throw fibroblasts into the mix, and the entire landscape changes -- literally. Plevritis mapped the treated tumor models and saw that post-treatment, the cancer cells and fibroblasts were generally left intact in the same amount. But they had rearranged themselves.
"That spatial reorganization appears to have given rise to drug-resistance," said Plevritis, the William M. Hume Professor in the School of Medicine. "It was like changing the furniture in the room, then finding the exits are blocked."
sources-science daily
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