An NCI-designated Comprehensive Cancer Center
By Abe Rosenberg | December 5, 2019
Chen-Shiuan Shiuan Chen, Ph.D.
If the future of cancer treatment lies in precision medicine — individualized drugs for each patient and malignancy, developed at the cellular level — then a team of researchers led by City of Hope scientists has just moved the science a significant step forward.
 
Using tools that didn’t exist a decade ago, researchers have demonstrated — with greater precision than ever — how external elements such as certain toxic chemicals can fundamentally change a cell’s composition and behavior in ways that may lead to cancer.
 
“We’re showing that cancer is not always the result of ‘defective’ genes,’” said Shiuan Chen, Ph.D.
chair and professor, Department of Cancer Biology, and the Lester M. and Irene C. Finkelstein Chair in Biology. “Environmental factors play a role, and now we have this detailed mechanism that shows how cells are affected.”
 
That “detailed mechanism” is single-cell RNA sequencing, or “scRNA-seq,” a relatively new process with considerable advantages over older, less precise and more biased methods, like gene expression microarrays. scRNA-seq produces reams of digital data, is more versatile and was previously unavailable but now made possible by advances in techniques to analyze single cells and in bioinformatics analysis, a field in which City of Hope has invested heavily.
 
“It’s a new, very exciting technology, and it’s still evolving,” said Chen.
 
In this study, the first of its kind in the area of environmental carcinogenesis, Chen and his team focused on breast cancer that strikes women who are going through menopause, “a critical window of [cancer] susceptibility,” he explained, “when normal hormone levels drop” and the mammary glands become super-sensitive to any added estrogen or estrogen mimics in the environment.
 
Because millions of women do exactly that — they take estrogen to deal with side effects of menopause — it made sense to examine any cellular changes this may cause. Several studies link estrogen therapy to increased risk of breast cancer, but the exact cellular mechanism isn’t fully understood.
 
Using mouse models, the researchers deployed scRNA-seq to examine changes in menopausal mammary gland cells when they are exposed to increased levels of estrogen (E2).
 
At the same time, they also looked at cellular changes caused by the presence of chemical compounds known as polybrominated diphenyl ethers (PBDEs). Once commonly used as flame retardants, PBDEs have been banned in the U.S. since 2004, but they can linger in the body for many years after exposure.
 
Mammary glands are complex structures with many different varieties of cells, and scRNA-seq made it possible to examine all of them. Several displayed profound changes in this study, especially when E2 and PBDEs were both present. Some cells grew faster. Others changed their pathways or physical parameters, making it easier for cancer to take hold. Still others, like immune cells, saw those immune properties altered.
 
“Our findings support that E2 + PBDE increase the risk of developing breast cancer through the expansion of estrogen-responsive luminal epithelial cells and immune modulation,” wrote Chen in the study, which was published in the journal Communications Biology on Nov. 5.
 
Understanding how an individual cell changes is a vitally important step, said Chen, because this knowledge “can help us identify new targets and design drugs that will attack those targets.”
 
“When we can more precisely identify the site of the [cancer] action,” he continued, “we can further refine our treatments and be more selective.”
 
The scRNA-seq process that enables this deep cellular dive is growing rapidly in popularity, a fact recognized by the National Institutes of Health, which funded this study. NIH funding has been trending toward scRNA-seq technology for several years, and now constitutes the majority of grants, outpacing studies using microarrays.
 
Chen and his colleagues see many more potential applications for scRNA-seq going forward. Several important studies are already underway, examining cancer at different stages of development and also moving past mouse models to look at human tumors, especially those that tend to recur or resist conventional treatment.
 
It’s especially gratifying, Chen pointed out, to do this work at City of Hope because of the vast and diverse resources he can draw upon, all together on the same campus and all united by a spirit of teamwork.
 
“City of Hope is unique for its core facilities, from imaging to genomics and much more.” Unlike other institutions with less infrastructure and staff knowhow, “We don’t have to reinvent the wheel here.”

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