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Unveiling the Interplay Between Extrachromosomal DNA Spatial Organization, Epigenetic Landscape, and Transcriptional Regulation with Single-Molecule Precision

Award Number: K99CA308829
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Unveiling the Interplay Between Extrachromosomal DNA Spatial Organization, Epigenetic Landscape, and Transcriptional Regulation with Single-Molecule Precision - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $166,968 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	1	7/28/2026	NEW	$166,968
														Subtotal = $166,968

Grand Total All Awards = $166,968

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Unveiling the Interplay Between Extrachromosomal DNA Spatial Organization, Epigenetic Landscape, and Transcriptional Regulation with Single-Molecule Precision

Award Number: K99CA308829

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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