Single-Cell Sequencing and Complex Cancer Genome Analysis for Clinical Parameters and Personalized Therapy

Ann Nguyen:
Hello, everyone. Welcome to this podcast from Cambridge Healthtech Institute for the Next Generation Dx Summit, which runs August 19th through the 21st in Washington, DC. I'm Ann Nguyen, associate conference producer. We have with us today one of our speakers from the Single-Cell Sequencing Conference, Dr. James Hicks, Research Professor of Cancer Genomics at Cold Spring Harbor Laboratory. Jim, thank you for giving us some of your time today.

James Hicks:
My pleasure.

Ann Nguyen:
You've had two tenures at Cold Spring Harbor: in the 70’s and since 2004. What led you from yeast molecular genetics to genomics and epigenomics of breast cancer, to single-cell sequencing now?

James Hicks:
Actually, there is not much motivational difference between what I did in yeast genetics, which was looking at single-cell responses. I'm known for mating site switching, and the way I approached the problem was actually with a microscope and figuring out ways to make single cells reveal their phenotype one at a time and watch their lineage as they switched, which meant sitting in the laboratory tearing cells apart with a micromanipulator every two hours for all night long and several days at a time. What I wanted to do when I changed, when I left Cold Spring Harbor, was to make my research more clinically oriented. Yeast is a model system I really wanted to move into clinically relevant research. That led to biotechnology, and then my second stint at Cold Spring Harbor after the genome was completed and there was a way to really dive into genetics at the mammalian cell level. That led to looking at cancer at a finer and finer level, to the point where now we're actually getting back to where I was before, which is micromanipulating individual cells to see what makes up that tumor and what makes up the cells that are circulating in a metastatic cancer in the blood. It's not very different in motivation, but it's the only way I really feel comfortable knowing what is going on in a process is to look one cell at a time.

Ann Nguyen:
What are the advantages of single-cell genomic analysis for ultimately personalizing therapies for patients with cancer and other treatable conditions, and how are you addressing the disadvantages?

James Hicks:
The advantages are due to the fact that cancer is heterogeneous in almost all of its forms. Some of it is obvious at the clinical level when telltale genes for therapy like HER2 are unequally represented in primary tumors and metastases, or unevenly distributed across tumors. But what we find is that, genomically, tumors are variously heterogeneous, and that heterogeneity and that ability to change their basic genomic skeleton is related to their aggressiveness, because they can respond more easily to drug treatment and become resistant. Also, the heterogeneity means that you may look for a specific marker, one or two markers, in a tumor preparation, but we can look at the whole genome for amplifications and co-lesions and gene fusions all at once. The advantage for doing single cells in the newest form of personalized therapy, which is to use fluid biopsies or blood draws where cancer cells are present in the blood but only at one in a million for example, compared to the blood cells, means that whatever method you use to pull the cancer cells out, they're going to be rare cells and you're only going to get one or two or three, or maybe even up to ten or twelve. That means that you have to be able to do the genetics on a single- or few-cell level. The biggest disadvantage of course, besides the trouble of getting single cells, is that it can be relatively expensive, so our methods are to use highly multiplex sequencing putting hundreds of cancer cells on a single sequencing lane using barcodes that distinguish them by making the cost of sequencing distributed over hundreds of cells and bringing it down to 20 to 30 dollars a cell, which makes it possible to actually be a clinical trial, which we are right now where we're sampling blood draws from 800 patients in a clinical trial sponsored by the Southwest Oncology Group.

Ann Nguyen:
What will be the main focus of your presentation at the Single-Cell Sequencing Conference on August 21st?

James Hicks:
The main thing will be on using genomics as an indication of both of the potential complexity of tumors or cancers as represented in the blood, but also the ability to interpret that data, derive clinical parameters either from specific markers or from the whole genomic state of the data - that is, the heterogeneity and the flexibility of the tumor - and make that into a clinical parameter that can be scored for prognosis or for predictive markers for therapy. It's a combination of biomarkers and technology.

Ann Nguyen:
Jim, thank you again for sharing your thoughts and experiences into this rising area of research.

James Hicks:
You're very welcome.

Ann Nguyen:
That was James Hicks of Cold Spring Harbor Laboratory. He'll be speaking at the Single-Cell Sequencing Conference during the session "Tips ‘N Tricks for a New Sequencing Frontier," at the upcoming Next Generation Dx Summit, taking place August 19th through the 21st in Washington, DC. I'm Ann Nguyen; thanks for listening.

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