The worldwide community of patients affected by Basal Cell Carcinoma of the skin (BCC) is larger than that of any other cancer. While BCC is rarely lethal, currently available treatment strategies often leave patients with disfiguring scars on their faces, heads, and necks. Moreover, the high recurrence rates of BCC require patients to be conscious of tumor growth throughout the entirety of their lives. This presents two primary research needs for the BCC field at large: 1) more effective treatment strategies that can circumvent the need for surgical resection and 2) strategies to prevent the re-growth of BCC for existing patients. This thesis describes efforts towards addressing both needs with a focus on fundamental understanding of the driving forces in BCC pathology and intervention. The first focus is towards rational design of therapeutic strategies to inhibit the Hedgehog (Hh) signaling cascade, the primary oncogenic driver in BCC. Gli transcription factors, the ultimate regulators of Hh signaling, are an attractive target for therapeutic intervention. Cobalt complexes interact with the zinc binding loci of these transcription factors, altering secondary structure and DNA binding affinity. Chapter 2 describes a cobalt complex targeted to Gli and efforts towards delivering it intracellularly for inhibition of Hh pathology in an in vitro BCC assay. The second focus is understanding the process of early Hh activation in cellular systems to elucidate mechanisms connecting pathway activation to oncogenesis. Chapter 3 describes exogenous activation of Hh signaling at two different points in the pathway, mimicking two different mutations observed in BCC. Hh inhibitors are explored for their potential to prevent Hh activation in a cellular model of organogenesis. Further, the activation of Hh signaling is explored in normal human epidermal keratinocytes (NHEK), the population of cell in which BCC arises. Chapter 4 describes the development of more complex 2-dimensional and 3-dimensional cellular assays with the ASZ murine BCC cell line to evaluate established disease progression. The first assay explores transwell migration of ASZ cells through a porous membrane and response to Hh inhibition. The second explores the incorporation of ASZ cells into a 3-D organotypic model of the fully stratified human epidermis. The changes in tissue phenotype and pathology are explored in response to increasing cancer incorporation as well as Gli inhibition. Ultimately, the first reported 3D model of BCC is described that mimics pathology of patient BCCs and is responsive to Gli inhibition.

Creator

• Dukes, Meghan Ward

DOI

• https://doi.org/10.21985/n2-9nhh-8953

Subject

• Inorganic chemistry
• Biology
• Biochemistry

Language

• en

Alternate Identifier

• etdadmin_upload_923011
• http://dissertations.umi.com/northwestern:16188

Keyword

• zinc finger transcription factors
• 3D skin cancer model
• Basal Cell Carcinoma
• Gli transcription factors
• cobalt-Schiff base
• graphene oxide

Date created

• 2022-01-01

Resource type

• Dissertation

Rights statement

• In Copyright