by Georgetown University Medical Center
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. Working with their research collaborators, the
scientists found that 'enabler cells' comprise 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.
The finding appears online June 16, 2021,
in Cancer Research, a journal of the American Association for Cancer
Research."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, Ph.D., 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 diagnosis
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 CRISPR, a tool that allows for easy gene editing, made
this finding possible; it is a collaborative effort with researchers at The
Ohio State University and Hackensack University Medical Center's John Theurer
Cancer Center, a part of Georgetown Lombardi Comprehensive Cancer Center. These
tools aided the scientists in building on their knowledge of alternative
splicing, or cutting, of genes whereby a single gene can be spliced to code for
multiple proteins.
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,
Ph.D., 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."
This finding is particularly relevant in
triple-negative breast cancers which can be aggressive and hard to treat. These
types of cancer usually start as non-malignant tumors, called ductal carcinoma
in situ (DCIS), but in about 5 to 10 percent of women, they can quickly
progress to malignant tumors. The investigators found that AIB1-Delta4 is found
at increased levels in women with higher-risk DCIS.
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."