Nicholas E. Navin (Interest in intratumor heterogeneity (developing a…
Nicholas E. Navin
Interest in intratumor heterogeneity
developing a method to isolate tumor subpopulations and study aneuploidy evolution
developed a computational algorithm (PROBER) to study the clonal substructure of breast tumors at single cell resolution
developing a single cell genome sequencing method
Tumour evolution inferred by single-cell sequencing. Nature. 2011
developed a method called Nucleus-Sequencing (NUC-SEQ)
Future: to understand the role of clonal diversity in invasion, metastasis, and chemoresistance evolution in breast cancer.
1) In early stage breast cancers, using SCS methods to identify rare clones that escape the ducts and invade the surrounding tissues.
2) applying SCS methods to study the key intermediates of metastasis, circulating tumor cells (CTCs), with the goal of understanding their genetic relationship to the primary and metastatic tumors.
Perhaps the most immediate clinical application is non-invasive monitoring, in which single cell sequencing of CTCs can provide a ‘liquid biopsy’ of the primary and metastatic tumors to monitor therapy response.
3) using SCS methods to determine if rare chemoresistant subclones are pre-existing in the tumor mass, or alternatively, are induced in response to the therapeutic agent.
Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing. 2018, Cell
Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature. 2014
SNES: Single nucleus exome sequencing. Genome Biol. 2015
Copy number aberrations occurred early in punctuated bursts, followed by stable clonal expansions, whereas point mutations were acquired gradually over time, resulting in extensive genomic diversity.
By directly comparing copy number changes and point mutations, we discovered that two distinct molecular clocks were operating during tumor evolution.
We applied SNS to study copy number changes in breast tumors, revealing a punctuated model of chromosome evolution
Punctuated copy number evolution and clonal stasis in triple-negative breast cancer. Nat Genet 2016
SNS method was limited to generating about 10% physical coverage of a single cell’s genome, which was sufficient for measuring large-scale (54 kb) copy number changes, but insufficient for resolving mutations at base-pair resolution.
However, the initial difficulty we faced was that these processes were driven by point mutations and indels, which required high-coverage single cell data.
The method we developed was called Single-Nucleus-Sequencing (SNS)
PROBER: Oligonucleotide FISH probe design software. Bioinformatics. 2006
Therefore, it was not possible to accurately reconstruct tumor evolution, which required a large number of genomic markers.
It soon became clear that genome-wide single cell sequencing data were needed, despite the formidable technical challenge it presented at the time.
This approach could resolve intratumor heterogeneity at single cell resolution, but it was limited to reporting copy number aberrations at targeted regions in the genome.
Although these data on tumor subpopulations were informative, they still reflected a complex admixture of tumor cell genomes.
Inferring tumor progression from genomic heterogeneity. Genome Res. 2010
During this time, we discovered the existence of normal copy number variants (CNVs) in the human population, and I become enthralled with the question of whether genomic diversity existed within tumor cell populations.
Large-scale copy number polymorphism in the human genome. 2004, Science
the tools needed to study this problem did not exist.
established an independent research laboratory