Clinical OMICS

MAY-JUN 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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www.clinicalomics.com May/June 2018 Clinical OMICs 27 The work conducted today for basic research using single-cell analysis techniques will very likely be used to improve clinical diagnosis, treatment and monitor- ing. Shalek's co-authored a paper in Science Translational Medicine last year stated that single-cell RNA sequencing (scRNA-seq), in particular, has the potential to "empower clinical implementation of personalized medicine." Currently, single-cell DNA sequencing (scDNA-seq) is not as easy to perform as scRNA-seq. That's because a single cell can have hundreds of copies of a particular gene, while DNA only has two copies (one from each chromosome). Yet while scDNA-seq is in its infancy, scRNA-seq is in its ado- lescence, with multiple companies coming to market with technologies designed to create libraries for scRNA-seq (see sidebar, page 29). Employing these, researchers can now pre- pare sequencing libraries of thousands or tens of thousands of cells. Leveraging scRNA-seq, researchers are addressing previously intractable problems, including characterizing the evolution of cancer and the attributes of tumor cells that cause therapeutic resistance, revealing the complexity of the nervous system, and honing the genes that allow a parasite to cause disease. Characterizing Cancer Despite its promise, a lack of spatial-temporal context is one of the challenges to making the most of single-cell analysis techniques. For example, information on the location of cells is particularly important when looking at how a common form of early-stage breast cancer, called ductal carcinoma in situ (DCIS) progresses to a more invasive form, called invasive ductal carcinoma (IDC). "Exactly how DCIS inva- sion occurs genomically remains poorly understood," said Nicholas Navin, Ph.D., associate professor of Genetics at the University of Texas MD Anderson Cancer Center. Navin is a pioneer in the field, developing one of the first methods for scDNA-seq. Cellular spatial data is critical for knowing whether tumor cells are DCIS or IDC. So, Navin developed topo- graphical single-cell sequencing (TSCS). Navin and a team of researchers published their findings in February 2018 in Cell. "What we found was that, within the ducts, mutations had already occurred and had generated multiple clones and those clones migrated into the invasive areas," Navin said. Navin and his colleagues are also using single-cell tech- niques to study how triple-negative breast cancer, becomes resistant to the standard from of treatment for the disease, neo-adjuvant chemotherapy. In that work, published in an April 2018 online issue of Cell, using scDNA-seq and scRNAseq, Navin and his colleagues found responses to chemotherapy were pre-existing, thus adaptively selected. However, the expression of resistant genes was acquired by subsequent reprogramming as a result of chemotherapy. "Our data raise the possibility of therapeutic strategies to overcome chemoresistance by targeting pathways identified in this study," Navin said. Revealing Complexity The authors of research published in 2017 in Genome Biol- ogy also identified lineage tracing as one of the technologies that will "likely have wide-ranging applications in map- ping developmental and disease-progression trajectories." In March researchers published an online study in Nature in which they combined single-cell analysis with a lineage tracing technique, called GESTALT (genome editing of syn- thetic target arrays for lineage tracing), to define cell type and location in the juvenile zebrafish brain. The combined technique, called scGESTALT, uses CRIS- PR-Cas9 to perform the lineage tracing and single-cell RNA sequencing to extract the lineage records. Cas9-induced mutations accumulate in a CRISPR barcode incorporated into an animal's genome. These mutations are passed onto daughter cells and their progenies over several genera- tions and can be read via sequencing. This information has (continued on next page) "As the technologies become more stable, there will be a lot of opportunities for clinical applications." —Nicholas Navin, Ph.D., MD Anderson Cancer Center Stocktrek Images / Getty Images

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