Cancer gene discovery and immunosurveillance studies using Sleeping Beauty mouse models
Authors
Laura Marie Rogers
Institution
University of Iowa
Country
United States
Year
2013
Journal
Dissertation - Iowa Research
Abstract
Cancer is the second leading cause of death in the United States. The
majority of cases are caused by sporadic somatic mutation, which leads to
cellular transformation over time. Therefore, cancer gene identification is a major
focus of current research efforts. Understanding how key driver mutations result
in cancer could lead to the design of better targeted therapies.
The Sleeping Beauty (SB) transposon system can be used to identify
driver mutations in a variety of tumor types. SB mutagenesis mimics the
sporadic accumulation of somatic mutations found in spontaneous human
cancers. This system also has an additional benefit over chemical
carcinogenesis models in that key cancer gene candidates are easily identified
with high-throughput sequencing and subsequent bioinformatic analysis. Using
SB, our lab recently identified a novel oncogene involved in non-melanoma skin
cancer called Zmiz1, the biological function of which is not well studied.
A major focus of my thesis work was to characterize Zmiz1 and its role in
skin cancer. This gene encodes a protein with predicted E3 SUMO ligase activity.
My work has provided the first evidence firmly establishing an oncogenic role for
Zmiz1 in cutaneous malignancy, thereby generating a novel transgenic mouse
model of skin carcinogenesis. Importantly, we observed tumor-specific
overexpression of an endogenous ZMIZ1 isoform in human squamous cell
carcinomas.
Non-melanoma skin cancer is the most common malignancy worldwide,
and it disproportionally affects immunosuppressed patients. One proposed
explanation for this is the concept of tumor immunosurveillance, whereby the
immune system suppresses tumor growth. When the immune system is
compromised, transformed cells can develop into tumors. However,
immunocompetent people also develop cancer, despite an intact immune system.
It is thought that while the immune system is keeping transformed cells from
forming a tumor, it simultaneously influences the acquisition of new mutations
that eventually allow escape from immune detection and clearance. This
process, called immunoediting, is widely believed to be dependent upon the
adaptive immune system and another focus of my research was studying
immunoediting mechanisms using SB mutagenesis.
Subtle differences were observed in the SB-induced mutation spectra of
tumors generated in immunocompetent mice and immunocompromised mice,
suggesting that some level of lymphocyte-dependent immunoediting of tumors
had occurred. However, the adaptive immune system was not effective in
suppressing tumor formation, which is in contrast with previously published data.
My work represents an independent and original assessment of the
immunoediting process, and cautions against reliance on a single animal model
to study this area of cancer biology.