Inherited DNA Repair Defects Disrupt the Structure and Function of Human Skin.

Parinda A Mehta, Susanne I Wells, Stella M Davies, Melinda Butsch Kovacic, Kakajan Komurov, Paul F Lambert, Dorothy M Supp, Bidisha Pal, Mary C Bedard, Kasiani C Myers, Sonya Ruiz-Torres, Adam Lane, Timothy M Chlon, Mathieu Sertorio, Adam S Nelson, Sharon Sauter, Kathryn A Wikenheiser-Brokamp, David P Witte, Marion G Brusadelli

Journal: Cell stem cell 2021;28(3):424-435.e6

PMID: 33232662

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Abstract

Squamous cell carcinoma (SCC) is a global public health burden originating in epidermal stem and progenitor cells (ESPCs) of the skin and mucosa. To understand how genetic risk factors contribute to SCC, studies of ESPC biology are imperative. Children with Fanconi anemia (FA) are a paradigm for extreme SCC susceptibility caused by germline loss-of-function mutations in FA DNA repair pathway genes. To discover epidermal vulnerabilities, patient-derived pluripotent stem cells (PSCs) conditional for the FA pathway were differentiated into ESPCs and PSC-derived epidermal organotypic rafts (PSC-EORs). FA PSC-EORs harbored diminished cell-cell junctions and increased proliferation in the basal cell compartment. Furthermore, desmosome and hemidesmosome defects were identified in the skin of FA patients, and these translated into accelerated blistering following mechanically induced stress. Together, we demonstrate that a critical DNA repair pathway maintains the structure and function of human skin and provide 3D epidermal models wherein SCC prevention can now be explored.

Address: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Division of Clinical Operations, Medpace, Cincinnati, OH 45227, USA.; Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.; Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pathology & Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.; Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Research Department, Shriners Hospitals for Children, Cincinnati, OH 45229, USA.; McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; Division of Oncology Discovery, Champions Oncology, Inc., University Plaza Dr #307, Hackensack, NJ 07601, USA.; Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Rehabilitative, Exercise, and Nutrition Sciences, University of Cincinnati College of Allied Health Sciences, Cincinnati, OH 45267, USA.; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: [email protected].

DOI: 10.1016/j.stem.2020.10.012

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https://antibodies.cancer.gov/detail/CPTC-SERPINB3...

MeSH Terms: Carcinoma, Squamous Cell, Cell Differentiation, Child, DNA Repair, Fanconi Anemia, Humans, Skin