“This told us the whole cast of players — who is where, what they are doing, and who they are talking with,” Khavari said. “No one has ever looked at individual cells in concert with where they are and how they are arranged in space.”

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.

‘Paving the Way for Invasion’

“These TSKs are leading the charge from a special niche environment at the edge of the tumor,” Khavari said. “There they can talk not only to the other cancer cells, but also to cells in the surrounding environment, paving the way for cancerous invasion into surrounding tissue. When we knocked out the ability of these cells to communicate, we stopped the growth of human squamous cell carcinomas that had been transplanted into mice.”

The researchers are now investigating whether their findings extend beyond squamous cell carcinomas.

“Are these tumor-specific cells a feature of most or all epithelial cancers?” Khavari said. “We’re not sure, but we can see that people whose cancers expressed high levels of genes associated with these cells had poorer outcomes.”

The researchers also are interested in learning how to use what they’ve learned in the study to create new, targeted therapies.

“Cancer really remodels the immune system to shut it down,” Khavari said. “Our study shows that the TSKs recruit Tregs, which form a barrier between the tumor and the surrounding tissue and create an immune-suppressed environment. It’s becoming obvious that successful cancer therapies will have to not just attack the tumor cells, but also find a way to activate the immune system and get it to stop tolerating the cancer.”