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RSPO1-mutated fibroblasts from non-tumoural areas of palmoplantar keratoderma display a cancer-associated phenotype

  • Investigative Report
  • Published:
European Journal of Dermatology

Abstract

Background

R-spondin (RSPO)1 is a fibroblast-secreted protein that belongs to the R-spondin protein family which is essential for reproductive organ development, epithelial stem cell renewal and cancer induction or suppression. RSPO1 gene mutations cause palmoplantar hyperkeratosis with squamous cell carcinoma (SCC) of the skin, 46XX sex reversal and true hermaphroditism.

Objectives

To characterize RSPO1-deficient skin fibroblasts derived from two patients with mutations in RSPO1, with palmoplantar hyperkeratosis, recurrent SCC and 46XX sex reversal, to provide further insight into disease-related skin tumourigenesis.

Materials & Methods

Fibroblast cultures from non-tumoural palmoplantar skin biopsies were established to evaluate features and properties that may be altered at cancer onset, i.e. proliferation, extracellular matrix contraction and invasion, as well as TGF-β and matrix metalloproteinase (MMP) secretion.

Results

Fibroblasts demonstrated increased proliferative potential in vitro, a high level of collagen contraction and invasion by SCC cells, release of high levels of pro-inflammatory and pro-fibrotic TGF-β, and increased expression of MMP1 and MMP3. Analysis of the expression of selected proteins associated with RSPO1-activated pathways confirmed sustained activation of the TGF-β signalling pathway and indicated a loss of TGF-β inhibitory feedback. Also, treatment of fibroblasts with a recombinant RSPO1 protein aggravated this proinflammatory phenotype, suggesting caution in designing therapeutic strategies based on restoration of protein function.

Conclusion

Our findings indicate that fibroblasts from RSPO1 -mutated patients behave similarly to cancer-associated fibroblasts. Chronic inflammation and fibrotic changes in palmoplantar skin may play a role in SCC development and recurrence, possibly by irreversibly activating the tumourigenic phenotype of fibroblasts.

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Acknowledgments and disclosures

Acknowledgments: SCC cells were kindly provided by Professor James G. Rheinwald (Department of Dermatology, Brigham and Women’s Hospital, Harvard Skin Disease Research Center, Boston, MA, USA). We thank Dr. Laura Panacchia for her collaboration with cell culture experiments. In memory of Dr. Liliana Guerra who died on August 23rd, 2020. Financial support: This work was supported by the Italian Ministry of Health (5 PER MILLE 2013 and RICERCA CORRENTE 2019 1.1) to LG. Conflicts of interest: none.

Author information

Authors and Affiliations

  1. Laboratory of Molecular and Cell Biology, IDI-IRCCS, Rome, Italy

    Elena Dellambra, Sonia Cordisco, Vittoria Proto, Carola Valente, Massimo Teson, Daniele Castiglia & Liliana Guerra

  2. Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy

    Sonia Cordisco

  3. Plastic Surgery Division, IDI-IRCCS, Rome, Italy

    Ezio M. Nicodemi

  4. Rare Skin Disease Center, IDI-IRCCS, Rome, Italy

    Biagio Didona

  5. Medical Genetics Unit and Laboratory of Medical Genetics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy

    Claudia Cesario & Elisa Pisaneschi

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  1. Elena Dellambra
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  3. Vittoria Proto
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Correspondence to Elena Dellambra.

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Dellambra, E., Cordisco, S., Proto, V. et al. RSPO1-mutated fibroblasts from non-tumoural areas of palmoplantar keratoderma display a cancer-associated phenotype. Eur J Dermatol 31, 342–350 (2021). https://doi.org/10.1684/ejd.2021.4066

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  • DOI: https://doi.org/10.1684/ejd.2021.4066

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