Developmental shape-shifting is key to cancer's ability to spread and evade immune defenses

Developmental shape-shifting is key to cancer's ability to spread and evade immune defenses

Just as people tend to become stuck in their ways as they grow older so too do cells. Neurons in the brain don't one day decide to become heart cells; skin cells repair wounds with skin cells rather than kidney cells. Cancer cells, on the other hand, are like perpetual teenagers. They're constantly trying on different identities and roles, which is partly what makes them so hard to control. In research published February 10 in Nature Medicine , a team of scientists at Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine reports that this developmental shape-shifting is key to cancer's ability to spread (metastasize) and interact with the body's immune defenses. We've known for a while that cancer cells tend to become more developmentally primitive, or stem cell-like, as they grow. What we were able to do in this study is identify the specific cell types that form primary tumors and compare them to those that make up distant metastases." Ashley Laughney, cancer biologist and the study's first author Ashley Laughney conducted the work as a postdoctoral fellow at the Sloan Kettering Institute and is now an assistant professor of physiology and biophysics at Weill Cornell Medicine. Focusing on lung cancer, the team discovered that the cell types in primary tumors and metastases fall along a spectrum of cells that regenerate injured tissue. The cell types in cancer that has spread are even more primitive than those in a primary tumor. The findings bring a deeper understanding of cancer metastasis, says Joan Massagué, Director of the Sloan Kettering Institute and a co-corresponding author on the paper. "These results focus our attention on the key role of regenerative cell types in recreating tumors in new locations," he says. "More and more, we are understanding that cancer cells co-opt normal developmental and wound-healing pathways to further their own ends." It's a devious strategy but one that opens avenues for potential treatment, he explains. The study was a collaborative effort and benefited from the expertise of SKI Computational and Systems Biology Program Chair Dana Pe'er, the paper's other co-corresponding author, and MSK physician-scientist Charles Rudin. A spectrum of primitive states In January 2020, the Massagué lab showed that markers of wound healing can be used to follow cancer cells as they detach from a primary tumor and spread to another location. The lab also found that isolated tumor cells are able to go undetected in the body by taking on certain properties of stem cells. In this new study, the team used human tissue samples and mouse models to characterize the identities and behavior of tumor cells at each step of the journey -- from the primary tumor through the breaking off of individual tumor cells to full-blown metastases. They discovered a range of cell types along this path that mirrored those involved in lung development. The scientists identified these cell types by combining two techniques. The first is called single-cell RNA sequencing (scRNA-seq). It allows investigators to measure which genes are turned on in thousands of individual cells at the same time. The team performed scRNA-seq on more than 40,000 individual cells from 17 samples obtained from people with lung cancer being treated at MSK. They then used advanced computational methods to interpret this head-spinning amount of data. Dr. Pe'er brought her team's computational expertise to the challenge. The result was a map of the full range of cell types present in normal tissue, primary lung cancers, and lung cancer metastases. From this analysis it was clear that the pattern of cell types in primary tumors was recognizably different than that of cell types in metastatic tumors. Related Stories



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