NIH grant: Unveiling the Interplay Between Extrachromosomal DNA Spatial Organization, Epigenetic Landscape, and Transcriptional Regulation with Single-Molecule Precision (1K99CA308829-01)

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NIH grant 1K99CA308829-01: Unveiling the Interplay Between Extrachromosomal DNA Spatial Organization, Epigenetic Landscape, and Transcriptional Regulation with Single-Molecule Precision
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Yanbo  Wang. Award: $166968.
Start: 2026-08-15T00:00:00.
Project Summary
Oncogene amplification is one of the most common genetic alterations in cancer, playing a central role in
tumorigenesis. A major mechanism of oncogene amplification is extrachromosomal DNA (ecDNA), which is
present in nearly 20% of cancer patients and found across half of all cancer types. Patients with ecDNA-positive
tumors have significantly shorter survival compared to those without ecDNA. Despite its prevalence and strong
association with poor treatment outcomes, there is no approved treatment targeting ecDNA-positive cancers.
Developing such treatments requires identifying the unique and actionable features of ecDNA.
Two unique features of ecDNA warrant special attention because they are seemingly paradoxical. On one hand,
ecDNA harbors some of the most accessible chromatin, driving exceptionally high oncogene expression. On the
other hand, ecDNA molecules preferentially cluster at the nuclear periphery, a transcriptionally repressive
environment. The underlying mechanisms remain elusive to study due to the lack of experimental approaches
capable of deciphering the molecular heterogeneity of ecDNA and linking its spatial organization to oncogene
expression.
To address this technical gap and investigate the mechanisms underlying these seemly paradoxical features of
ecDNA, I will develop single-molecule multi-omics sequencing methods, which enable spatially resolved
epigenetic profiling (chromatin accessibility and DNA methylation) of individual ecDNA molecules. I will then
apply these technologies in tightly controlled experimental ecDNA models to answer the following questions:
What are the epigenetic and functional consequences of ecDNA locating at the nuclear periphery (Aim 1)? And
how does ecDNA establish an exceptionally permissive chromatin environment for high-level transcription
despite its preferential localization at the nuclear periphery (Aim 2)? Completion of this research will not only
provide mechanistic and functional insights into the two seemingly paradoxical features of ecDNA but also
evaluate the feasibility of perturbing ecDNA spatial organization as a therapeutic strategy. Additionally, this
research will introduce innovative single-molecule sequencing approaches that can be broadly applied to cancer
genomes with molecular heterogeneity.
This research will be conducted under the guidance of a world-class mentoring and advisory team at Stanford
University, including Dr. Paul Mischel, a leading figure in ecDNA cancer research, Dr. Michael Snyder, a world-
renowned expert in multi-omics technologies and genomics, and Dr. William Greenleaf, a pioneer in epigenomics,
along with collaborators specializing in single-molecule sequencing, bioinformatics and cell engineering. The first
half of each aim will be completed during the K99 phase, and the technologies, discoveries, and training acquired
during this period will establish a strong foundation for launching my independent research lab.

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