Researchers from Huntsman Cancer Institute (HCI) at the University of Utah, in collaboration with the Salk Institute for Biological Studies, have developed a single-cell resolution atlas of genes that control the formation of breast tissue.
The field has long been working to understand how various tissues are formed and organized, particularly in the mammary gland, however, knowledge at the level of individual cells is sparse, noted Benjamin Spike, PhD, HCI cancer researcher and Assistant Professor of Oncological Sciences at the University of Utah.
To fill this void, a research team, led by Spike, analyzed thousands of individual breast cells to gain a better understanding of developmental kinetics and mechanisms of lineage specification (Cell Rep 2018; doi:10.1016/j.celrep.2018.07.025).
“It has been recognized for a long time that various cancers, including breast cancer, share characteristics with the early development of their tissue of origin,” Spike explained. “And so, we predict that learning more about early tissue development would provide an untapped opportunity to identify the molecular regulators of development that are taken over by cancers.”
Working alongside Geoffrey Wahl, PhD, Professor at the Salk Institute, and others, Spike and his team isolated breast cells from mice during different stages of breast tissue development.
“We utilized new genomic sequencing technology to determine the gene expression pattern for each cell in those tissues,” Spike said. “We then used computational approaches to analyze this data to identify the regulators of those cells as well as to pinpoint relationships between various cell types and what cancers look like to see if we could identify molecular programs being co-opted by the cancers for their growth.”
Next, researchers used a series of biological assays, including growth assays, to begin testing which of all those candidates could be good targets for controlling normal cells and tumor cells, according to Spike.
The research team uncovered hundreds of potentially critical genes for further study as regulators of normal and cancerous development, which could lead to targets for treating certain breast cancers.
“We provided a detailed atlas of the cell states in developing breast tissue,” explained Spike. “This is a quite comprehensive resource of what cells look like across the course of development and the genes that are associated with various states of cellular differentiation and function.
“We then defined shared characteristics between various cells and cancers arising in human breast tissue,” he continued. “This provides us some potential study material and ways to understand the pathways that are being used and what we might target to treat those cancers or to control a particular stage of cellular development.”
In addition, Spike noted that the study also revealed a more fundamental finding in regards to how tissues in organisms are organized. “When you look at the cells that make up a tissue, like the mammary gland, at this very high resolution, you come to appreciate that every cell is an individual,” he said. “This heterogeneity of the cells is a very interesting observation, probably reflecting each cell's potential and integration of cues from its local environment.”
These findings “provide a useful resource for illuminating mammary cell heterogeneity, the kinetics of differentiation, and developmental correlates of tumorigenesis,” study authors concluded.
“This research promises new targets for these cancers, including genes involved in specialized cellular metabolism that are shared between early breast development and certain breast cancers,” Spike explained, in a statement. “The data from the study gives new insights about the organizing principles of tissues and the molecular definitions of the cell types comprising them.
“The research shows that breast cells in early development that are not fully differentiated into mature cell types activate more genes, resulting in mixed profiles and expression of some genes in unexpected breast cell types.”
What are researchers focused on next? “There is still a lot of work to do,” noted Spike. “We have identified a large list of candidate regulatory pathways and genes that we can now start going through to determine which ones are actually critical to cell growth, and which ones may be differentially used by tumors versus normal development.
“We will also look at what pathways are only used in early development, but are resurrected in the cancer cells,” he continued. Given the ongoing challenge of targeting cancer cells without impacting the normal cells, Spike noted that these pathways, in particular, have the potential be excellent targets. “We should be able to block them without effecting the other cells of the adult.”
The potential impact of this atlas goes far beyond the work of Spike and his team. “With this database published as a resource, many other labs will be able to go through the data as well and identify different candidates that they want to test in functional assays,” Spike said. “The hope is that using this atlas, new therapies can be designed for breast cancers, and maybe other cancers as well, that don't currently have good molecularly targeted therapies.”
Catlin Nalley is associate editor.