# FA pathway activities in the normal and transformed epidermis

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $363,713

## Abstract

ABSTRACT
Human epidermis serves as a critical barrier against mechanical, chemical, radiation and infectious insults in
the external environment. Keratinocytes are the main cell type in this stratified tissue, and are organized into
basal stem and progenitor cells, and the more superficial differentiated progeny. Epidermal homeostasis and
integrity are tightly regulated and critical for human health. Squamous cell carcinomas (SCCs) are perhaps a
prime example of epidermal homeostasis gone awry. Both sporadic and inherited forms of SCC are associated
with mutations in the 21 genes of the Fanconi anemia (FA) pathway, which participate in the repair of DNA
crosslinks. Close associations between the FA pathway and SCC development point to important roles for this
pathway in keratinocytes and epidermis – roles that have not yet been studied, but will be investigated here
using FA patient populations and tools to study keratinocyte biology. These tools include human iPSC-derived
keratinocytes and 3D organotypic epithelial rafts isogenic for FA genes, as well as skin biopsies from FA
patients (vs. controls) that are uniquely available at Cincinnati Children's Hospital. Our translational studies
build on recent data demonstrating cell adhesion, cytoskeletal and membrane defects in FA-deficient
keratinocytes, skin biopsies, and 3D organotypic rafts. The defective keratinocytes were also hyper-motile, and
invasive particularly when transformed – and the invasive phenotype depended on the activities of the DNA
damage sensor kinase DNA-PK and the small GTPase Rac1, as well as ganglioside accumulation. The
overarching hypothesis is that FA pathway loss leads to the assembly of a Rac1 signalosome in membrane
domains enriched for gangliosides (eg lipid rafts), and consequent phenotypes that are reminiscent of
epithelial-mesenchymal-transition (EMT-like). Aim 1 tests the hypothesis that the FA pathway regulates
adhesion/integrity and cell motility in the normal epidermis through ganglioside accumulation and DNA-
PK/Rac1 signaling. Aim 2 directly tests the impact of FA loss on transformation, defines the FA-pathway-
dependent flux of ganglioside biosynthesis and its role in sustaining SCC growth and progression. The results
will identify a) signaling and lipid-based mechanisms whereby nuclear DNA repair machineries control the
integrity of human epidermis, and b) biomarkers and therapeutic targets for the prevention and treatment of
SCC development in patients with acquired and inherited FA pathway deficiencies.

## Key facts

- **NIH application ID:** 10216196
- **Project number:** 5R01CA223790-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Susanne I Wells
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $363,713
- **Award type:** 5
- **Project period:** 2018-08-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216196

## Citation

> US National Institutes of Health, RePORTER application 10216196, FA pathway activities in the normal and transformed epidermis (5R01CA223790-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10216196. Licensed CC0.

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