Page 31 - Annual Report 2020

skin carcinogenesis. In the past several years, my lab has conducted multi-omics studies to define UV-induced genetic and epigenetic alterations
in skin cells. We have identified master regulator genes of skin UV response as potential targets
for developing mechanism-driven targeted ap- proaches for skin cancer prevention and treatment. Additionally, we have defined a novel UV gene expression signature (UVGES) panel consisting
of conserved UV target genes. This UVGES panel has a significant clinical potential to address the unmet need of sensitive molecular tests to quantify skin UV damage and skin cancer risk. To validate the clinical utility of the UVGES panel, we are collaborating with dermatologists to collect clinical samples for multiplex gene expression analysis using the Nanostring nCounter platform. Prelim- inary results show that a subset of the UVGES genes are specifically associated with high-risk skin cancer subtypes. We will continue to optimize the biomarker panel to improve its sensitivity and specificity. The long term goal of this project is to develop a cost-effective biomarker-based test to enable patient risk stratification for targeted cancer prevention and treatment.
Project 2. Role of hairless in skin homeostasis, stem cell maintenance, immune regulation, and UV-induced skin carcinogenesis
The hairless gene encodes a transcription co- regulator that is essential for skin homeostasis and hair follicle cycling. Several lines of evidence suggest that hairless functions as a master regulator of skin homeostasis via controlling the expression of its target genes involved in cell proliferation, apoptosis, stem cell function and immune response. We recently reported that hairless is an epigenetic regulator with histone
demethylase activity. Mutational inactivation of hairless alone can dramatically increase tumor incidence and burden in response to chemical induction or UV radiation. In human skin squa- mous cell carcinomas (SCCs) and other cancer types, we found frequent deletions of the hairless gene. Moreover, hairless expression is frequently down-regulated in human SCCs but not benign actinic keratosis lesions. Through ChIP-seq studies, we have identified several hairless target genes that play important roles in cancer development. These findings clearly suggest that hairless is a pivotal tumor suppressor gene and prompted us
to further define the anti-tumor activity of hairless, its target genes, and the role of histone methyl- ation in regulating epidermal homeostasis, stem cell activity, and skin immunity. We are performing studies to elucidate the mechanism by which hair- less regulates immune gene activity and to probe the role of IL-36 signaling in skin inflammation and tumorigenesis. Ultimately, we hope to elucidate the genetic and epigenetic pathways through which hairless regulates skin homeostasis and to iden- tify new hairless target genes that modulate skin inflammation and cancer development.
Project 3. Role of hairless mutation in breast cancer development
The initiation and progression of breast cancer (BC), traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic defects. Research over the past two decades has demonstrated that BC is an extremely heterogeneous disease, comprising many subtypes that involve distinctive molecular pathogenesis. This heterogeneity underscores the importance of a comprehensive understand- ing of the genetic and epigenetic defects asso- ciated with BC biologic heterogeneity, in order to
develop individualized and targeted therapies to attack the specific mechanism(s) underpinning specific cancer subtypes. We have compelling evidence that hairless functions as a tumor suppressor gene during skin cancer development. Surveying the human cancer genomics database reveals that genetic mutations of hairless occur at a high frequency in BC patients who suffer from more aggressive BC subtypes. Moreover, analyzing the Cancer Cell Line Encyclopedia mutation database found that 17 out of 59 human BC cell lines harbor hairless gene copy number loss. Most of these hairless-deficient BC cell lines are also derived from aggressive BC subtypes, suggesting an intriguing role of hairless in the development of aggressive BCs. However, its mechanism of action is unclear. In light of its novel function as an epigenetic regulator with histone demethylase activity, we are investigating the function and mechanism of hairless in BC pathogenesis. The overarching goal of this proj- ect is to define the anti-tumor function of hairless in BC development and to identify the genetic/ epigenetic pathways through which hairless exerts its tumor suppressor function.
Meeting presentations:
1. A dynamic panel of UV signature genes for risk stratification of cutaneous actinic keratosis and squamous cell carcinoma subtypes. International Transplant Skin Cancer Collaborative (ITSCC) Workshop, May 2020.
2. Identification of novel UV targets and pathways in skin photocarcinogenesis. American Society for Photobiology Meeting. June 2020.
THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 31