Date of Award
12-20-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The landscape of spatial biology research has transformed drastically in recent years allowing a comprehensive understanding of cellular organization and molecular mechanisms in various biological context. This thesis presents three complementary studies that advance our understanding of spatial organization in normal tissue biology and tumor evolution, utilizing cutting-edge spatial multi-omics approaches. The first study presents a comprehensive investigation of kidney sexual dimorphism across the lifespan, integrating six distinct technological platforms: single-nucleus transcriptomics, epigenomics, Visium spatial transcriptomics, Xenium single-cell resolution spatial transcriptomics, conventional immunofluorescence imaging, and co-detection by indexing (CODEX) multiplexed protein imaging. This multi-modal approach reveals that proximal tubules exhibit the most pronounced sex-biased gene expression patterns, which emerge after three weeks of age and are intricately associated with hormonal regulations. The study elucidates the mechanistic involvement of androgen and estrogen in sex-biased gene expression regulation in the kidney, providing fundamental insights into organ-specific sexual dimorphism. The second study examines the spatial organization and evolution of tumors through an extensive analysis of 131 tumor sections from 78 cases spanning six cancer types. By combining Visium spatial transcriptomics with matched single nuclei RNA-seq, CODEX, as well as other bulk RNA and DNA-based modalities, this work introduces two key concepts: “tumor microregions”—spatially distinct cancer cell clusters separated by stromal components—and “tumor spatial subclones”—microregions sharing identical genetic profiles. The study reveals how these spatial subclones exhibit varying oncogenic activities, unique interactions with their local microenvironments, and distinct three-dimensional tumor architectures. The third study assembles a multi-omic cohort of primary and metastatic prostate cancer, employing advanced single-cell resolution spatial transcriptomics platforms such as Xenium, VisiumHD, and CosMx to identify prostate cancer transition markers. By integrating morphological grading from corresponding H&E histological images, transition markers such as TRPM8 and PCA3, enriched in GP3 regions, and FMOD, enriched in GP4 regions, were identified. Additionally, single-cell spatial expression patterns revealed evidence of oncogene ERG expression in benign luminal epithelial cells, suggesting that genetic events may precede morphological changes. In metastatic prostate cancer, two distinct subtypes of neuroendocrine prostate cancer (NEPC) were identified, characterized by differential androgen receptor expression, potentially influencing their response to androgen deprivation therapy (ADT). Together, these studies demonstrate the power of integrative spatial multi-omics approaches in revealing new biological insights that are unattainable through individual modalities alone. The findings advance our understanding of normal tissue organization, tumor evolution, and their interaction with the local microenvironment, establishing a foundation for future therapeutic strategies and biological discoveries
Language
English (en)
Chair
Li Ding
Committee Members
Feng Chen; Hong Chen; Kooresh I. Shoghi; Tao Ju