Telomeric Regulation of Chromosomal Instability In Colorectal Cancer

<p>Telomere dysfunction drives chromosomal instability (CIN) during the transition from benign adenoma to malignant adenocarcinoma. While CIN provides a mutator mechanism for cancer-relevant genomic events, its role in shaping tumor biology during carcinogenesis is not well understood. Here, we explored the molecular and biological impact of telomere dysfunction and associated CIN <em>in vivo</em> in a faithful model of CRC. <em>In vivo </em>lineage tracing revealed that CIN increased neoplastic cell competition and clonal expansion through accelerated differentiation of neighboring stem cells, resulting in increased number of adenomas and decreased survival in CIN-high <em>Apc^min </em>mice. Mechanistically, CIN represses EZH2 leading to upregulation of secreted Wnt antagonists, which resulted in a growth advantage to CIN-high neoplastic cells. Correspondingly, pharmacological activation of intrinsic WNT signaling enhanced intestinal stem cells fitness, leading to reduced neoplastic cell clonal expansion and adenoma burden. Thus, the CIN-EZH2-WNT axis enhances intestinal cancer initiation in the nascent tumor microenvironment, providing a preventive strategy for patients harboring germline <em>APC </em>mutations.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2023

Authors dc:creator

• LaBella, Kyle
• A LaBella, Kyle
• <p>0000-0002-0473-9262</p>

Contributors dc:contributor

• Ronald A. DePinho, M.D.
• Stephanie Watowich, Ph.D.
• Yejing Ge, Ph.D.

• Telomere
• colon cancer
• DNA damage
• EZH2
• Wnt
• stem cell
• Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1308

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2365