Investigating 3D Nucleome Architecture Alterations in Lung Adenocarcinoma

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Wang, Siyuan

Abstract

The three-dimensional (3D) genome plays a crucial role in gene regulation and normal development process, yet how its structural alterations drive cancer progression and therapy resistance remains poorly understood. Understanding these changes is essential for identifying novel biomarkers and therapeutic targets. Here, we use genome-wide chromatin tracing to construct the first comprehensive 3D genome atlas of lung adenocarcinoma, revealing a previously unrecognized structural bottleneck during early tumor evolution. We find that despite substantial heterogeneity, single-cell 3D genome features can distinguish histologic cancer states, underscoring their potential for diagnostic applications. Moreover, targeted therapies such as EGFR inhibitors are often compromised by acquired drug resistance, yet the underlying mechanisms extend beyond genetic mutations. By profiling osimertinib-resistant lung cancer cells, we uncover widespread chromatin reorganization and compartmental shifts, demonstrating that 3D genome remodeling acts as a key epigenetic driver of resistance. Furthermore, we establish a framework for studying 3D genome alterations in clinical FFPE tumor samples, providing a foundation for deeper investigations into tumorigenesis. These findings position 3D genome dynamics as a critical but underexplored regulator of cancer evolution, emphasizing the urgent need to integrate spatial genome mapping into cancer research for improved diagnosis, prognosis, and therapeutic strategies.

This document is currently not available here.

Share

COinS