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Single-cell genomics drive progress toward human breast cell atlas development




A notable finding of this project was the presence of “not one, but two populations of fibroblasts,” Dr. Swarbrick said, noting that fibroblasts are typically discussed as a single entity.

“This is arguing that there are at least two major types present within the breast, and almost every case has these populations present at roughly equal amounts,” he said.

This is of particular interest, because it has been shown in prior studies that targeting fibroblasts can have therapeutic outcomes.

“So we think this is a very important population within the tumor microenvironment,” he added.

With respect to gene expression features, CAF-1 is dominated by signatures of extracellular matrix deposition and remodeling, which “look like the classic myofibroblasts that we typically think of when we study cancer-associated fibroblasts.”

“In contrast, the CAF-2 population ... have what appears to be quite a predominant secretory function, so we see a lot of cytokines being produced by these cells, but we also see a very high level of expression of a number immune checkpoint ligands,” he said, adding that his team is actively pursuing whether these cells may be undergoing signaling events with infiltrating lymphocytes in the tumor microenvironment.

The signatures for both CAF types are prognostic within large breast cancer data sets, suggesting that they do actually have an important role in disease, he noted.

Markers for these cells include ACTA2, which was previously known to be a marker, and which is almost exclusively restricted to CAF-1, and the cell surface protein CD34 – a progenitor marker in many different cellular systems, “which is actually beautifully expressed on the CAF-2 population” as demonstrated using CITE-seq.

“So we’re now using this as a way to prospectively identify these cells, pull them out of tumors, and conduct biologic assays to learn more about them,” he said.

The immune milieu

“We’re in the age of immunotherapy, and this is an area of huge interest, but we have a long way to go in making it as effective as possible for breast cancer patients,” Dr. Swarbrick said. “I believe part of that is through a very deep understanding of the taxonomy.”

RNA data alone are useful but insufficient to fully identify subsets of immune cells due to a “relatively low-resolution ability to resolve T cells.”

“But because we’re now using the panel of 125 antibodies in parallel, we can now start to use protein levels to split up these populations and we can start to now identify, with higher resolution, more unique populations within the environment,” he said, noting that the availability of protein data not only helps identify subtypes, but is also therapeutically important as it allows for certainty regarding whether the protein target of therapeutic antibodies is expressed on the surface of cells.

Ultimately the hope is that this effort to build a multi-omic breast cancer atlas will continue to drive new discoveries in personalized medicine for breast cancer, Dr. Swarbrick concluded, adding that the field is moving fast, and it will be very important for labs like his and the Navin Lab to communicate to avoid needlessly duplicating efforts.

“I think it’s going to be really exciting to start to put some of these [findings] together,” he said.

The MD Anderson project is funded by the Chan Zuckerberg Initiative as part of its work in supporting the Human Cell Atlas project. Ms. Seth reported having no disclosures. Dr. Swarbrick’s research is funded by the Australian Government/National Health and Medical Research Council and the National Breast Cancer Foundation. He reported having no relevant disclosures.

SOURCE: Seth T et al. SABCS 2018, Abstract GS1-02; Swarbrick A et al. SABCS 2018, Abstract GS1-01

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