Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Investigative Medicine
First Advisor
Lu, Jun
Abstract
HOX genes, fundamental in directing embryonic development, are implicated in the spatial organization and functional differentiation of tissues. Their influence, traditionally investigated during early developmental stages, has been noted in a wide variety of malignant processes, albeit at a single gene level in the context of individual cancer types. Given that the HOX genes represent a complex and interrelated network, a unified model evaluating the role of the entire set of HOX genes in cancer has not yet been achieved. Similarly, an overarching model that considers HOX gene patterns in multiple cancer types is absent. This study aims to discover the pattern of HOX gene expression in human adult tissues and cancer, and evaluate their function. To systematically investigate the expression of HOX genes across a broad spectrum of human adult tissues and to assess their involvement in the pathogenesis of cancer, we sought to map the landscape of HOX gene expression, exploring how these developmental genes are repurposed in adult physiology and malignancy. Performing computational analyses of gene expression data from the GTEx and TCGA databases, along with targeted CRISPR-Cas9 and CRISPR activation (CRISPRa) screens, we sought to elucidate the patterns and functional implications of HOX gene expression. Our study unveiled distinctive HOX gene expression patterns across human adult tissues, implicating their continued role beyond embryonic development. Notably, a pattern emerged showing a correlation between altered HOX gene expression and cancer, with many cancers exhibiting a shift towards expression profiles characteristic of normal posterior body tissues, a phenomenon we refer to as posteriorization. We found posteriorization to be associated with higher tumor grade and worse survival outcomes across a spectrum of cancer types. Experimentally, the functional significance of HOX genes in cancer was further explored using CRISPR-Cas9 mediated loss-of-function (LOF) and CRISPRa gain-of-function (GOF) screens. These screens targeted specific HOX genes to assess their impact on cell viability in several cancer cell lines. The LOF screen demonstrated cell-line-specific responses to HOX paralog group disruption, providing evidence of both suppressive and advantageous effects on cancer cell viability. Additionally, the GOF screen provided insights into how overexpression of certain HOX genes can suppress cancer cell growth, depending on the cellular context. These findings underscore the complexity of HOX gene functions in cancer, revealing that their roles are highly context-dependent and can vary significantly between different tumor types and cellular environments. In conclusion, this investigation sheds new light on the expression patterns of HOX genes in adult human tissues and their reprogramming in cancer. The discovery of posteriorization across various solid tumors underscores the profound impact of developmental gene expression patterns on cancer biology. Furthermore, our experimental findings highlight the importance of context in the regulation and effects of HOX genes in malignancy. By advancing our understanding of the molecular underpinnings of cancer through the lens of developmental biology, this work paves the way for potentially novel approaches to cancer diagnosis and treatment that exploit the dysregulation of HOX genes.
Recommended Citation
Kurbatov, Vadim, "Mapping and Functional Characterization of HOX Gene Expression Patterns in Human Normal Tissue and Solid Tumors" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1402.
https://elischolar.library.yale.edu/gsas_dissertations/1402
