Skin cancer growth driven by subset of cellular masterminds

June 26, 2020

An elite population of cancer cells marshal at the leading edges of a growing skin tumor to guide its metastasis and help it evade the body’s immune system, researchers at the Stanford University School of Medicine have found. They do so by communicating not just with other cancer cells — goading them to divide and spread — but also with surrounding normal cells, recruiting specialized cells that dampen the immune response and others that promote cancer invasion.

Blocking these cancer masterminds’ communication abilities significantly slowed the growth of human tumor cells transplanted into laboratory mice, suggesting that similar targeted therapies may one day be successful in human cancers. For the study, the researchers focused on a common skin cancer called squamous cell carcinoma, which affects more than 1 million people each year in the United States. Although most people are treated successfully, about 1 percent will eventually die from the disease. Squamous cell carcinoma belongs to a class of cancers known as epithelial cancers, which includes about 90 percent of all human cancer types.

To understand more about how epithelial cancers grow and metastasize, researchers combined several techniques to analyze the architecture, cell types and gene expression profiles at the single-cell level of squamous cell carcinomas from 10 people — in effect, not just generating a molecular fingerprint for each cell but also precisely locating it and its neighbors within the three-dimensional space of the growing tumor.

They then compared their findings with normal skin from the same people whom the cancers were collected from. The findings are the first time such a comprehensive, integrated analysis has been conducted at the level of single cells, and it gives a never-before-seen glimpse into the cellular interactions both inside and outside the tumor.

The researchers found that the carcinomas differed from normal skin in their types of cells in one main way: In addition to mirroring the normal cell types, they had an additional subpopulation of cells Khavari and his colleagues called tumor-specific keratinocytes, or TSKs. Intriguingly, these TSKs were found primarily at the leading edges of the growing tumor, and they expressed genes that recruit specific cell types to the cancer site.

Some of the recruited cells are regulatory T-cells, or Tregs, which dampen the body’s natural immune response to prevent overreactions that can lead to autoimmune disorders. Others are cells called cancer-associated fibroblasts, which destabilize the extracellular matrix around the tumor and promote metastasis. Still others are endothelial cells, which line the interior of blood and lymph vessels.

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