Revealing the Mechanisms of Tumorigenesis Through Multi-Omics Analyses

Over the past two decades, our understanding of cancer has undergone a paradigm shift. What was once thought of as an abnormal population of proliferating cells, is now recognized as a complex system shaped by dynamic interactions across genomic and environmental scales. Advances in research have revealed a multifaceted etiology of tumorigenesis, extending from just hallmark oncogenic mutations to include large-scale genomic alterations, transcriptomic dysregulation, epigenetic reprogramming, and external influences such as environmental carcinogens and oncogenic pathogens. This heterogeneity, coupled with genomic evolution and multilayered crosstalk within tumor ecosystems, highlighted the complexity of cancer. The advancement of high-throughput sequencing technologies has revolutionized cancer research, enabling comprehensive profiling of tumors through integrative multi-omics approaches. Large-scale cohort studies leveraging these tools have identified diverse cancer phenotypes, offering insights into the molecular diversity of malignancies. Yet, a critical challenge remains: the inability to systematically trace tumor evolution from the very beginning to progression in humans, which hinders the development of targeted therapeutic strategies. To address this challenge, my research employs controlled in vitro models to dissect early tumorigenic mechanisms of two understudied oncogenic drivers which also lack clinically actionable therapies: viral infection induced Merkel cell carcinoma (MCC) and transient centrosome loss induced chromosomal instability (CIN) in prostate cancer (PCa). By integrating multi-omics profiling with network biology and machine learning algorithms, this work systematically maps the potential molecular mechanism driving malignancy in these cancers. For MCC, I identified that viral infection rewires key signaling circuits that force normal cells transform into neuroendocrine state tumor cells; in PCa, I defined stratification signatures linked to transient centrosome-loss associated CIN. These findings not only demonstrate foundational mechanisms of tumorigenesis but also reveal novel targets for precision therapies, advancing translational strategies for two malignancies with unmet clinical needs.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Graduate College

Grantor dc:publisher

The University of Arizona.

Year dc:date.issued

2025

Author dc:creator

• Yang, Jiawen

Advisors dc:contributor.advisor

• Padi, Megha
• Rogers, Gregory

Committee members dc:contributor.committeemember

• Yao, Guang
• Paek, Andrew
• Gutenkunst, Ryan

• cancer biology
• chromosomal instability
• computational biology
• regulatory network
• virology

Statement dc:rights

• Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10150/677511

OAI identifier oai:identifier

oai:repository.arizona.edu:10150/677511