Title:Tumor analysis turning point

Just a small number of cells found in tumors can enable and recruit other types of cells nearby, allowing the cancer to spread to other parts of the body, report Georgetown Lombardi Comprehensive Cancer Center scientists. Findings show that “enabler cells” make up about 20 percent or less of the cells in an aggressive tumor. Their small numbers may account for why they are often missed when bulk tissue analyses are used to inform therapeutic decisions.

“Our novel finding goes beyond the common understanding of cancer progression as one modeled on Darwinian selection where ‘survival of the fittest’ means the predominant type of cell in a tumor dictates its outcome,” noted Anna Riegel, PhD, professor of oncology and pharmacology at Georgetown Lombardi and the corresponding author of the study. “This could have major implications for our understanding of how best to diagnose and treat certain cancers, as blocking key cancer-promoting subpopulations of cells might be a way to defeat the cancer.”

The advent of advanced gene sequencing technology, coupled with the use of gene-editing CRISPR, made this finding possible. The study used alternative splicing, or cutting, of genes whereby a single gene can be spliced to code for multiple proteins. The collaborative effort included researchers at Ohio State University and Hackensack University Medical Center’s John Theurer Cancer Center, a part of Georgetown Lombardi Comprehensive Cancer Center.

The researchers’ work using CRISPR in both zebrafish and mice zeroed in on cell subpopulations responsible for enabling metastasis. This led researchers to the discovery of a single RNA splicing event in the AIB1 (amplified in breast cancer 1) gene. One splice variant of the gene produced the AIB1-Delta4 protein, which was found to be responsible for promoting communication and recruitment of surrounding cells, eventually leading to metastasis.

“We propose that the detection of these enabler cells in early-stage breast cancers could predict which tumors are more aggressive and destined to metastasize,” said Ghada M. Sharif, PhD, research assistant professor at Georgetown Lombardi and first author of this finding. “Therapeutic targeting of vulnerabilities uncovered in the enabler cells, such as the splice variants, could represent a new approach to preventing malignant progression of breast cancer.”

The researchers’ next step will be to conduct various single cell analyses in human tissue samples. “We are at a turning point in how we analyze tumor samples,” said Riegel. “It was unthinkable and impractical just a few years ago to look at every single cell in a tissue sample. But technology is racing ahead, and we believe that in the next few years, looking at each cell will allow us to determine which cells, even if they are small in number, are truly driving cancer progression.