# Mechanisms regulating the early stages of UV-induced skin cancer

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $362,250

## Abstract

Project Summary: Cutaneous squamous cell carcinoma (cSCC) is the second most common
form of cancer with approximately 700,000 cases annually in the US leading to 3,000 deaths.
The incidence of cSCC will increase given an aging population with rising cumulative UV
exposure. In response to this epidemic, the Surgeon General issued a `Call to Action' detailing a
plan to address the growing epidemic of UV-induced skin cancers. One component of this
strategic plan to decrease UV-induced skin cancer is to perform research that defines the
mechanisms of UV-induced skin cancer. The transition from keratinocyte to cSCC by UV
radiation involves formation of precancerous lesions, called actinic keratoses (AKs) and
carcinoma in situ (SCCIS). AKs and SCCIS are hypothesized to arise from UV-induced
mutations in keratinocytes that lead to cell populations with aberrant growth and differentiation.
To better understand how UV irradiation alters keratinocytes and promotes the early stages of
skin cancer, we performed laser capture microdissection of SCCIS and adjacent UV-exposed
epidermis, isolated genomic DNA and generated libraries for whole exome sequencing. This
novel approach permits a precise comparative genomic analysis of mutations in UV-exposed
epidermis and SCCIS. Our exomic sequencing data demonstrate low frequency UV-signature
loss-of-function mutations in Notch in 60% of epidermal samples and heterozygous clonal
mutations in 40% of SCCIS samples. Nucleoporins (Nups) were also frequently mutated in 80%
of epidermal libraries and 100% of SCCIS libraries. These data show that UV-signature
mutations in Notch and Nups are more common than mutations in known oncogenes such as
p53 or RAS. The goal of this proposal is to show how Notch and Nup mutations promote the
early stages of UV-induced skin carcinogenesis leading to SCCIS. The biological impact of UV-
irradiation on Notch-deficient clones will be studied using genetically engineered mice and
engineered human keratinocytes in xenograft models. The biological significance of Nup
mutations in UV-irradiated skin will be determined using mice with an epidermal deficiency in
the Nup Elys, which links the nuclear pore complex to chromatin. In addition, human
keratinocytes will be engineered to express mutant Nups and subjected to UV-irradiation in a
xenograft model. The aims of this proposal will yield novel insights into the role of Notch and
Nup mutations in skin cancer and will provide important insights into designing rational
approaches to treat SCCIS.

## Key facts

- **NIH application ID:** 10376752
- **Project number:** 5R01ES028114-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** John T. Seykora
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $362,250
- **Award type:** 5
- **Project period:** 2018-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376752

## Citation

> US National Institutes of Health, RePORTER application 10376752, Mechanisms regulating the early stages of UV-induced skin cancer (5R01ES028114-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10376752. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*