Tumors are not homogenous blobs of cancer cells — far from it. Every tumor contains billions of cells, many of which aren’t cancerous, with diverse genetic features resulting from the tumor’s evolution over time.
The question is: How does a single cell with a few mutations evolve into the complex ecosystem at the heart of a devastating disease? The answer not only has implications for our fundamental understanding of biology, but it could also explain why patients may relapse after initially responding well to therapy.
Cancer evolution captured the imagination of Nicholas Navin, Ph.D., early in his research career and continues to drive his work.
“I became really interested in genetic diversity within tumors, but there wasn’t much data available at the time,” says Navin, a geneticist at The University of Texas MD Anderson Cancer Center. “I started by cutting tumors into big chunks, but I never got the full picture of how the mutations in one cell could contribute to a tumor’s evolution. That’s when I realized — despite there being no tools to accomplish this at the time – we were going to need to do single-cell analysis.”
His ongoing curiosity led him to pioneer single-cell sequencing technologies that have since transformed cancer research in ways that benefit both scientists and patients. Navin and his laboratory continue to develop innovative single-cell analytical approaches.
Breakthroughs like this are central to MD Anderson’s Strategy, as the institution strives to drive high-impact discovery research focused on addressing unmet medical needs and improving the lives of patients around the world.
Decoding complex single-cell data
Single-cell RNA sequencing enables researchers to profile gene expression from thousands of individual cells in a tumor, but the resulting data is quite complex and it’s not easy to pinpoint the cancer cells within a given sample.
“With single-cell RNA experiments, we would get clusters of cells — some tumor cells, some immune cells — and it was quite hard to identify the tumor cells,” Navin says. “One feature that 90% of all cancers have is aneuploid copy number changes, or an abnormal chromosome number. We found that you can use single-cell RNA data to measure the copy number of the genome and have a way to identify aneuploid tumor cells.”
With this, the CopyKAT (copy number karyotyping of aneuploid tumors) tool was born. This computational approach can accurately differentiate between cancer cells and the many normal cells found within a tumor using single-cell RNA sequencing data.
Through the integrated research programs at MD Anderson, Navin’s team has deployed CopyKAT in several institutional collaborations. Navin also established MD Anderson’s SINGLE CORE, a core facility supporting single-cell sequencing research and collaborations funded by the Cancer Prevention & Research Institute of Texas (CPRIT).
These collaborations have enabled Navin and his team to identify rare subpopulations within triple-negative breast cancers that have unique genetic alterations, providing a path for potential therapeutic implications. The team also is applying CopyKAT to study clinical trial samples from patients with triple-negative breast cancer to better understand variations in treatment response.
Improved techniques dive deeper into DNA
Recognizing that previous single-cell DNA sequencing techniques often required several days to complete, Navin’s team developed an approach capable of improving both speed and resolution.
This method, called Acoustic Cell Tagmentation (ACT), uses sound waves to rapidly transfer small volumes of liquid to perform enzymatic reactions and amplify DNA, which can shrink the overall time to just a few hours. In addition to faster throughput, the single-molecule resolution enables researchers to study chromosome evolution in new ways.
When leveraging this technique with collaborators, the researchers revealed for the first time that triple-negative breast cancer cells undergo continued genetic copy number changes after an initial burst of chromosome instability at the earliest stages of progression.
This new discovery has important implications both in the lab and the clinic. It provides valuable insight for researchers using breast cancer cells, suggesting that cultured cells will continue to evolve at a slow rate.
Further, the ongoing evolution of a cancer may explain why treatments are not always effective for triple-negative breast cancers. Navin’s team continues research to understand if the number of genetic changes present in a tumor can be used to predict clinical outcomes.
Driving discoveries to benefit patients
As Navin continues leading innovation in the field, the core reason for his work is the ultimate impact that it could have on patients with cancer. This is why he joined MD Anderson — to conduct groundbreaking science that answers fundamental biological questions, while also staying deeply connected to leading clinicians who can help advance these discoveries for clinical impact.
“At the end of the day, my colleagues and I want to make an impact for patients in biomedicine,” says Navin. “Having this infrastructure where I can go next door to several of the world’s best breast cancer pathologists, and then across the street to surgeries that provide a broad range of human tissue samples — it affirms that the collaboration being done across our labs is for the service of the over 100,000 patients that come to MD Anderson every year. These patients provide the groundwork, motivation and direction for the research that is being conducted within our labs.”
MD Anderson has multiple faculty and research positions available across the spectrum of cancer science. Learn more about the exceptional research environment and available positions here.