Single Cell Technology Zooms In for Clearer View of High-risk Pediatric Cancers

Dec 10 2018

Single Cell Technology Zooms In for Clearer View of High-risk Pediatric Cancers

The voice of Kai Tan, PhD, rises and quickens when he considers the potential of single cell technology to zero in on pathogenesis of cancer and other diseases. He points to the attention this course of research is receiving via funding from organizations such as the National Cancer Institute (NCI) Moonshot Initiative and the Chan Zuckerberg Initiative’s Human Cell Atlas project. In fact, Dr. Tan is himself is a valued contributor to the single cell revolution, and his work will continue with a recent NCI grant for the development of a pediatric tumor cell atlas.

Dr. Tan, an investigator in the Center for Childhood Cancer Research (CCCR) at Children’s Hospital of Philadelphia and an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, and co-principal investigator Stephen Hunger, MD, chief of the Division of Oncology and director of the CCCR, were awarded a five-year research grant totaling $12.5 million to create the Center for Pediatric Tumor Cell Atlas as part of a 10-center  national consortium.

Dr. Tan and Dr. Hunger will work closely with other key investigators at CHOP such as pediatric oncologists Kristina Cole, MD, and Kathrin Bernt, MD; Angela Waanders, MD, MPH, neuro-oncology attending physician; and Adam Resnick, PhD, research scientist in the Department of Biomedical and Health Informatics. Additional off-site key investigators are Hao Wu, PhD, assistant professor of genetics, and Nancy Zhang, associate professor of statistics, both at University of Pennsylvania, and Kun Zhang, PhD, professor of bioengineering at University of California at San Diego.

The CHOP team is the only pediatric cancer group receiving the award on account of its world-class pediatric cancer researchers, large volume of patients, and unique ability to acquire biosamples of what is considered a rare disease — pediatric cancer. Their project is under the umbrella of the larger Moonshot Human Tumor Atlas Network (HTAN) that aims to generate atlases of a diverse cancer patient population and high-risk cancers.

Arresting the Most Deadly Cancers

Dr. Tan and his team will focus on three subtypes of pediatric malignancies that together account for more than 50 percent of all pediatric deaths from cancer: high-grade glioma, high-risk neuroblastoma, and very high-risk acute lymphoblastic B-cell precursor leukemia.

“We’re focusing on these because there is an urgent need [for more research] into those high-risk types,” Dr. Tan explained. “Molecularly, these cancers are different; their biggest commonality is the patient will die quickly after diagnosis.”

Further delving into the capabilities of single-cell technology, Dr. Tan noted one key to novel therapeutic development is understanding how the variety of cells that comprise a tumor — immune cells, mesenchymal cells, cancer cells — interact with each other. Additionally, gathering data on the genetic heterogeneity of the tumor cells will assist researchers in understanding the genetic mutations responsible for these malignancies.

“In the past, genomic technology could not distinguish a single cell from the bulk tumor sample,” Dr. Tan explained. “As a cutting-edge research initiative, the goal of HTAN is to use various types of single cell technology, combined with clinical samples, to truly understand the heterogeneity of the tumor clone evolution, and how the different types of cells in the tumor microenvironment interact throughout disease progression.”

As his team works toward a greater comprehension of two critical therapeutic transitions — premalignancy to primary cancer and primary cancer to relapse or drug resistance — the aim is to use that information to capture disease early in the process, develop diagnostic biomarkers to better stratify patients, and create more effective treatment strategies.

“If we can use molecular information from the single cell level to develop therapies, and to aid in prognosis or diagnosis, that would be the eventual goal,” Dr. Tan said.

Organizing Volumes

As Dr. Tan and colleagues prepared for the project’s kickoff meeting at NCI, he had some of the finer logistical points of such an enormous project on his mind. Representatives of the multidisciplinary, multi-institutional team of approximately 50 scientists from CHOP, University of Pennsylvania, and University of California at San Diego — oncologists, pathologists, surgeons, molecular biologists, computational biologists, and other colleagues — would gather to create a roadmap of how they would work as a cohesive group.

Among the topics to be covered were the technical challenge of acquiring clinical patient biopsy samples and delivering them quickly to the molecular biologists without disturbing the integrity of the sample, and a plan for the computational analysis of the volumes of genomic, molecular, and clinical data that will be generated over the course of the study.

“Once we gather the raw data, how do we know which cells share the same set of gene expression patterns?” Dr. Tan said. “Another challenge [to this research] is how to do efficient clustering. We will not only have a measurement of different genes, but various types of molecules inside the cells. So, the question becomes: How do we integrate the data to compare molecular signatures between tumor cells and immune cells, for instance.”

Overall, HTAN will generate a huge amount of genomic data, imaging data, and clinical data. Each center will initially process their own, then provide it to the HTAN data coordination center where it will be homogenized, combined, and presented to the research community, patient advocate groups, NCI, and … well, everyone. The end goal is three-pronged: an easily searchable, publicly available database; research community access to the computational tools utilized in the project; and access to biospecimens including tissue sections, viably frozen specimens, and patient-derived xenograft models.

The Long View

This five-year grant to support the pediatric tumor cell atlas is considered a pilot grant by NCI, though it’s already part of the larger HTAN project. The CHOP team is going to look at 20 patients for each of the three cancer subtypes. NCI’s vision is that once it has been determined how best to gather and house these data and biosamples, and the work begins to generate results that could be used for better treatments, targeted drugs, and more efficient prognosis and diagnosis, then the “pilot” could continue for another five years, according to Dr. Tan.

Even if the project does not go on, it will have spurred study in the single cell technology to zoom in for the clear, close-up view of tumor cells, instead of the previous blurred version gleaned from the study of bulk samples.

“I’m particularly excited about the power of single cell technology to allow us to start to address these questions — the heterogeneity in the microenvironment, how cancer clones dynamically evolve during treatment, and how this clonal evolution can contribute to drug resistance,” Dr. Tan said. “I’m very excited about the kind of promise that can deliver, and that excitement is shared by all the researchers. Right now, single cell technology is revolutionary, not only for cancer but other disease types.”