Characterizing the Inflammasome in Cutaneous Squamous Cell Carcinoma Open Access

Abstract

Cutaneous skin cancers are the most prevalent type of cancer found in humans. As the largest organ of the human body, the skin is predisposed to increased levels of mutagenesis, ultimately resulting in cancers. Basal (BCC) and squamous (cSCC) cell carcinomas are currently the most prevalent of all skin cancers, with cSCC having a higher mortality rate, especially at late stages. Although the most common mutagen, ultraviolet radiation, has been identified, molecular mechanisms surrounding the development and propagation of cSCC remains unclear. Specifically, the tumor microenvironment, in many cases, plays a significant role in promoting or reducing tumorigenesis. We previously showed that NLRP3 inflammasome activation in dermal fibroblasts is key to driving hyperproliferation and stem cell fate mis-specification under DNA damage. Here, we characterize the inflammasome, an component of the innate immune response, in cSCC via transgenic hyperactivation of KRas^G12D in the basal cells. We demonstrate that the inflammasome is indeed activated in the epidermis of cSCC in vivo as well as dermal fibroblasts, a result further validated via fluorogenic ASC-Citrine overexpression. Furthermore, using ex vivo whole tissue explantation of the epidermis, we demonstrated that the activation of the inflammasome in the epidermis is tissue-autonomous. Overexpression of KRas^G12D in dermal fibroblasts in vitro indicated that inflammasome activation due to KRas is not cell-autonomous. These surprising results suggest that inflammasome activation is present in KRas-mediated cSCC, laying the groundwork for in-depth studies to elucidate the exact molecular mechanism of this crosstalk.

Table of Contents

CHAPTER 1: INTRODUCTION                                                                                              1

CHAPTER 2: METHODS                                                                                                       14

CHAPTER 3: RESULTS                                                                                                          19

CHAPTER 4: DISCUSSION                                                                                                   34

References                                                                                                                               42

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Cell
Keyword	inflammasome skin squamous cell carcinoma
Committee Chair / Thesis Advisor	Lindsey Seldin, Emory University
Committee Members	Roger Deal, Emory University Matthew Weinschenk, Emory University

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