HMGB1 in EB-Associated Squamous Cell Carcinoma

Project Summary/Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease characterized by chronic wounds
and shortened lifespan due to a high incidence of early-onset squamous cell carcinoma (SCC). The highly
aggressive nature of SCC in RDEB patients warrants further mechanistic study. High mobility group box 1
(HMGB1) is a serum biomarker of disease severity in RDEB, but its role in tumorigenesis in patients with RDEB
has not been thoroughly investigated. HMGB1 is a chromatin-associated protein that functions in the nucleus as
a regulator of DNA replication and repair. In response to inflammatory signals, HMGB1 is secreted from the
nucleus and functions as a damage associated molecular pattern that stimulates the innate immune response.
The central hypothesis of this proposal is that depletion of nuclear HMGB1 in keratinocytes drives carcinogenesis
in RDEB by promoting inflammation and accelerating genome instability. This hypothesis will be tested through
two specific aims investigating the effects of sequestering HMGB1 in the nucleus. The first aim explores the
impact of altered HMGB1 localization on inflammatory response and genomic instability in RDEB keratinocytes.
The second aim evaluates the usefulness of small molecule inhibitors of HMGB1 secretion in preventing tumor
formation using an in vivo mouse model of RDEB. Successful completion of these aims will provide new
information on the biological function of HMGB1 in patients with RDEB SCC. The results of this study have the
potential to reveal new drug targets for a fragile patient population in desperate need of safe and effective
treatment options.
This proposal will be completed at the University of Minnesota under the co-mentorship of Dr. Jakub Tolar, a
physician-scientist and pediatric oncologist specializing in RDEB, and Dr. Anja-Katrin Bielinsky, an expert in
genome maintenance and DNA repair defects in the initiation of cancer. The complementary expertise of the co-
sponsors uniquely positions the candidate to complete the aims described in this proposal and achieve her goal
of becoming an academic pediatric hematologist-oncologist leading a research lab focused on examining
mechanisms underlying rare genetic diseases and cancer. The career development and fellowship training plans
outlined in this application build the foundation for a long and productive career investigating better treatments
for pediatric patients with complex and difficult-to-treat genetic conditions.

Grant Number: 5F31CA281039-03
NIH Institute/Center: NIH
Principal Investigator: Kacey Bui