Author ORCID Identifier

https://orcid.org/0000-0002-5728-8557

Date Available

12-19-2024

Year of Publication

2024

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

Advisor

Dr. Yekaterina Zaytseva

Co-Director of Graduate Studies

Dr. Tianyan Gao

Abstract

Globally, colorectal cancer (CRC) is the second leading cause of cancer related deaths. Currently, there is a growing incidence rate for individuals aged 20-49 years. Genetic and environmental factors contribute to the risk of this cancer. Early detection of CRC allows for the most effective treatment option in which surgical resection of the primary tumor occurs along with adjuvant chemotherapy. This therapeutic approach contributes to 5-year survival rate of 91%. However, surgical procedures and chemotherapy struggles against metastatic and relapsed CRC resulting in 5-year survival rate of 14%. Inefficacious treatments for relapsed and metastatic diseases emphasizes the need for more therapeutic or preventative strategies.

Altered lipid metabolism is a well-recognized feature of solid cancers, including CRC. Lipid metabolism plays a major role in overall survival through important processes, including membrane maintenance, energy homeostasis, and signal transduction. To adapt to stressful conditions and promote tumor growth, cancer cells utilize lipid metabolism to respond to metabolic changes through fatty acid uptake or de novo lipid synthesis. Fatty acid synthase (FASN), a multi-enzyme, is a great contributor and driving force in de novo lipid synthesis. In de novo lipid synthesis, FASN facilitates the synthesis of palmitate, which is further used for synthesis of more complex lipids. The overexpression of FASN contributes to CRC progression and metastasis in preclinical studies and contribute to poor patient outcome. Our laboratory has demonstrated that FASN contributes to CRC initiation through the alteration of metabolic and signaling pathways to promote adenoma formation in Apc/VillinCre (Apc/Cre) mouse model.

Cancer stem cells (CSCs) have been found to contribute to the development and progression of various cancers. CSCs utilize properties, like self-renewal and undifferentiation, to promote tumor growth and evade chemo-and radiotherapies. A prior study showed that FASN is required for 3D properties/anchorage-independent growth of

cancer cells. As forementioned, our laboratory identified the unique, important role of FASN in CRC initiation. Furthermore, gene enrichment analysis demonstrated that downregulation of Fasn in Apc/Cre model is associated with downregulation of pathways linked to cancer-associated signaling. Wnt/β-catenin pathway has a significant role in initiation and stemness maintenance in CRC. Wnt/β-catenin pathway was downregulated in adenomas with low FASN expression suggesting potential crosstalk between de novo lipogenesis and Wnt/β-catenin signaling pathway.

NOTUM is a carboxylesterase that removes palmitoleic acid from Wnt ligands, diminishing their binding affinity for their receptors, therefore downregulating Wnt signaling. However, a recent study demonstrated that mouse Apc mutant intestinal cells secrete Notum as a competitive strategy to outcompete wild type cells and promote CRC initiation. NOTUM was found to correlate with cancer stem cells and poor prognosis in CRC patients. Moreso, Notum was found to enhance stem-like properties in gastric cancer.

My studies have demonstrated that FASN contributes to stemness in CRC through upregulation of β-catenin activity and stem-like properties in multiple models, including CRC cells, human CRC organoids, Apc/Cre, and Apc/VillinCre-ERT2 (Apc/ERT2) mouse tissues and organoids. Moreso, my studies demonstrated the novel finding of FASN regulation of NOTUM expression and stemness via the Wnt/β-catenin pathway. Furthermore, pharmacological inhibition of NOTUM decreases viability and proliferation of CRC cells and adenoma organoids. Collectively, my studies suggest that FASN regulates stem-like properties via the β-catenin/NOTUM axis. Therefore, targeting FASN upstream of the β-catenin/NOTUM axis may be an effective preventative therapeutic strategy or early-stage treatment option for CRC.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.463

Funding Information

This study was supported by National Cancer Institute T32 CA165990 (C.O.K.) from 2022-2024.

This study was also supported by National Cancer Institute R01 CA249734 (Y.Y.Z.), National Cancer Institute R01 CA208343 (B.M.E.), and National Cancer Institute R01 CA284532 (B.M.E.) from 2021-2024.

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