Date of Award
12-6-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Aging is marked by the progressive decline of cellular and organ function. This process often manifests through DNA damage, epigenomic alterations, telomere shortening, and metabolic or mitochondrial dysfunction. As DNA damage and other stressors accumulate, cells take measures to prevent malignant transformation. One such measure is cellular senescence, a state of irreversible cell cycle arrest that halts the growth of pre-malignant cells. When cells are unable to enter senescence due to high levels of genomic alterations, they typically undergo apoptosis or necrosis. However, if mutations affect key driver genes, allowing cells to evade death, they may become malignant, continuing to divide, grow, metastasize, and ultimately harm surrounding tissue—leading to death if untreated. As cancer advances, it accumulates additional genomic alterations that drive its progression toward metastasis, the primary cause of cancer-related deaths. However, mutation alone does not fully explain cancer progression, highlighting the need to explore the role of epigenetic plasticity in this process. This dissertation offers a detailed examination of the epigenetic factors—both cis- and trans-regulatory elements—that contribute to cancer progression from normal tissue to primary tumors and, eventually, to metastasis. These findings emphasize the critical role of the epigenome in shaping cancer cell plasticity, where the coordination of enhancer accessibility and transcription factor binding with gene expression drives tumor evolution. While senescence plays a role in cancer prevention, the excessive accumulation of senescent cells can be harmful and even promote tumorigenesis. First, the buildup of these cells disrupts tissue structure, contributing to age-related organ dysfunction and diseases. Second, senescent cells secrete inflammatory proteins and extracellular matrix remodeling factors, driving systemic inflammation and creating an environment conducive to cancer. Conversely, cancer can also influence the levels of senescence in tissues. The tumor microenvironment can induce senescence in normal stromal cells within the tumor and potentially in surrounding tissues. Furthermore, cancer treatments—especially those involving DNA-damaging agents—can exacerbate senescence in normal tissues. In this dissertation, I provide the first comprehensive characterization of senescent cell populations in the human liver, examining their presence during normal aging and diseases such as fibrosis. I also elucidate senescent populations in the liver and tumor microenvironment in the context of metastatic colorectal cancer and systemic chemotherapy. These findings not only deepen our understanding of the molecular foundations of cancer progression and liver function decline but also offer potential targets for mitigating both processes by focusing on their shared epigenetic and senescence-related pathways.
Language
English (en)
Chair and Committee
Li Ding
Committee Members
David DeNardo; John Edwards; Michael Meers; Naresha Saligrama
Recommended Citation
Karpova, Alla, "Epigenetic Mechanisms and Senescence in Aging and Cancer" (2024). Arts & Sciences Electronic Theses and Dissertations. 3337.
https://openscholarship.wustl.edu/art_sci_etds/3337