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Single-Cell DNA Sequencing Weaves a Way Towards Personalized Cancer Treatment

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High-throughput single-cell analysis has been regularly acclaimed as a transformative technology for sequencing and a huge step towards the goal of personalized medicine. Over the last few years, a series of applications and techniques have been touted as a Big Step Forward. Tapestri, a sequencing platform developed by Mission Bio is the latest contender to announce itself. Tapestri has the heft of a peer-reviewed study, and the endorsement of some of the US’s largest cancer centers behind it – could Tapestri be the game-changer in DNA analysis we have been waiting for?

Bulk isn’t Always Best

The promise and potential of single-cell analysis is obvious. Bulk genomic sequencing, where the DNA or RNA content of entire tissues are analyzed at once, is often unable to separate out particular cell populations within these tissues, meaning variation between cell types is hard to identify. Looking at individual cells would provide us with a much more accurate picture of what is going on in our samples.

That’s all well and good, but when your study involves looking at thousands of cells, individual cell analysis can be pretty painful, as Koichi Takahashi, M.D. of the Department of Leukemia at the University of Texas MD Anderson Cancer Center, is well aware of.

Takahashi is co-lead author on the recent paper that announced Tapestri’s potential as an analysis platform for cancer cells. The study analyzed tumor cells from patients with acute myeloid leukemia (AML). “We worked with Mission Bio to perform single-cell DNA analysis on longitudinal samples from AML patients and genotyped up to 62 disease relevant loci across more than 16,000 single cells,” says Takahashi.

All in a Drop

The technology that enables Tapestri has been around for some time. The microfluidics-based method takes a suspension of cells and captures each individual cell inside a droplet. Each droplet contains a barcode which tags the cell’s genetic material, meaning later analysis can be tied to individual cells rather than just to a larger collection of cells. 

The technique has been widely used for conducting single-cell RNA sequencing but replicating the technique on DNA has proved more challenging, because DNA is tightly tied up within cells, attached to proteins like chromatin. Tapestri’s innovation is to add in proteases, enzymes that break down the chromatin tangling up DNA. 

The proteases are then inactivated, before the single-cell DNA is amplified using polymerase chain reaction (PCR). In their study, the Tapestri team showed that adding the protease step hugely increased the efficiency of the PCR amplification, thereby unlocking the later process of single-cell DNA analysis.

Taking a Targeted Aim at Tumors

Tumor cells have remained a challenging target for DNA analysis due to the amount of genetic variation within any particular tumor cell population. The Tapestri platform, says Takahashi, was able to overcome these problems in their study: “Mission Bio’s proprietary droplet microfluidic technology enables longitudinal monitoring of AML progression and insight (…) that is otherwise not possible with traditional sequencing methods.”

Tapestri’s other quirk is its use of targeted sequencing, focusing on particular regions of DNA rather than analyzing the entire tumor genome. This approach slashes the cost of Tapestri-based sequencing to a tenth of whole genome sequencing (WGS), say Mission Bio, making the sequencing of every cell in a tumor population feasible.

I asked Takahashi whether this targeted approach risks missing out some genetic information from the final analysis, and he pointed out that the WGS approach isn’t necessarily ideal when depth of analysis is key: “Whole genome sequencing of many single-cells would not only be prohibitively expensive at this time, but the depth of sequence coverage for the meaningful genomic loci would be lower and result in a reduced ability to accurately call genetic variants. Consequently, a targeted sequencing approach enables a higher resolution picture (Mission Bio claim a 50-fold increase in resolution over traditional sequencing technologies) of tumor heterogeneity with the sequence information needed to maximally impact our understanding of disease progression and choice of therapies during treatment.”

In Takahashi’s study, Tapestri’s single-cell analysis was used to explore the clonal architecture of the AML tumors – the family tree of mutations that cause certain cell lines to become dominant within a particular tumor. Unravelling the clonal architecture can be a potent tool in understanding how a cancer develops, and how likely a patient is to relapse.  Comparing Tapestri’s single-cell approach to a bulk approach, Takahashi and colleagues noted that one subclone, predicted by bulk analysis to make up nearly a quarter of the cellular content of a tumor, was actually revealed to make up just 1.7% when the tumor was analyzed with the single-cell approach.

Reading the Blueprints of Cancer

Tapestri’s pinpoint performance may help patients with other types of cancer, and Mission have even looked at investigating Tapestri’s potential to explore off-target effects in the omnipresent gene editing technique CRISPR. Takahashi’s focus remains on Tapestri’s potential in oncology: “We believe there’s great potential for this technology to increase our understanding of the complex clonal architecture of AML and other types of sister leukemias like Myelodysplastic syndrome (MDS) and Chronic lymphocytic leukemia (CLL). We’re also interested in applying Tapestri in a Minimal Residual Disease (MRD) setting (where small numbers of cancer cells remain in patients in remission). The Tapestri technology has very high sensitivity to clonal evolution, more sensitive than the current NGS or broad-based sequencing. As such, it can detect even minimal amounts of genetic mutation that remain after treatment, providing the potential to predict which patients might be subject to future relapse.”

Precision Medicine Meets Single-Cell DNA Analysis With Mission Bio

Mission Bio's Tapestri platform. Credit: Mission Bio

Most excitingly, Takahashi believes Tapestri’s technology could be a huge step towards developing personalized medical approaches to cancer treatment: “The ultimate goal is to make personalized medicine a widespread reality, and we’re talking a matter of years, not decades, from achieving that reality. Delivering on the promise of precision medicine depends on two major components: knowledge and action,” says Takahashi.

“To deliver on the ultimate goal, we need to first understand the clonal structure of cancer in a precise way,” he continues. “With the Tapestri platform, we receive unprecedented insight into that structure, and that advances us a step closer to this goal. From there, however, we have to apply those learnings to our treatments – this step is still in progress. To fully realize the goal of personalized medicine, we need to leverage the insight we've gained into the clonal structure of cancer, applying it to develop better treatment methods beyond chemotherapy and targeted molecular therapy. Once researchers and clinicians take advantage of this scalable platform solution, we’ll be one step closer to accelerating drug discovery, development, and delivery.”