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ResearchIn-Press PreviewCell biologyDermatologyInflammation Open Access | 10.1172/jci.insight.192890

TGF-β–mediated epithelial–mesenchymal transition of keratinocytes promotes fibrosis in secondary lymphedema

Hyeung Ju Park,1 Jinyeon Shin,1 Ananta Sarker,1 Mark G. Klang,2 Elyn Riedel,3 Michelle Coriddi,1 Joseph H. Dayan,1 Sarit Pal,1 Babak J. Mehrara,1 and Raghu P. Kataru1

1Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Research Pharmacy, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Park, H. in: PubMed | Google Scholar |

1Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Research Pharmacy, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Shin, J. in: PubMed | Google Scholar

1Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Research Pharmacy, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Sarker, A. in: PubMed | Google Scholar

1Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Research Pharmacy, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Klang, M. in: PubMed | Google Scholar |

1Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Research Pharmacy, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Riedel, E. in: PubMed | Google Scholar

1Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Research Pharmacy, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Coriddi, M. in: PubMed | Google Scholar

1Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Research Pharmacy, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Dayan, J. in: PubMed | Google Scholar

1Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Research Pharmacy, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Pal, S. in: PubMed | Google Scholar

1Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Research Pharmacy, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Mehrara, B. in: PubMed | Google Scholar |

1Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Research Pharmacy, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Kataru, R. in: PubMed | Google Scholar |

Published July 29, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.192890.
Copyright © 2025, Park et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 29, 2025 - Version history
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Abstract

Secondary lymphedema is characterized by fibrosis and impaired lymphatic function. Although TGF-β is a key regulator of fibrosis in this disease, the cellular mechanisms regulating this process remain unknown. Epithelial–mesenchymal transition (EMT), a mechanism by which TGF-β induces fibrosis in other skin diseases, is characterized by loss of epithelial cell markers and cellular polarity, upregulation of fibrotic gene expression, and gain of migratory capacity. Using clinical lymphedema biopsy specimens and animal models, we show that keratinocytes in the basal layer of the epidermis undergo EMT in lymphedematous skin, migrate into the dermis, and contribute to dermal fibrosis. In vitro studies using cultured primary human keratinocytes treated with lymphatic fluid from the affected limbs of patients with secondary lymphedema resulted in a TGF-β–mediated increased expression of EMT markers. We show for the first time that EMT is activated by TGF-β in secondary lymphedema and that this process plays an important role in regulating skin fibrosis in this disease.

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  • Version 1 (July 29, 2025): In-Press Preview
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