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Wnt-mediated interactions of tumor-initiating cells with a macrophage niche drive skin tumor formation

View ORCID ProfileSilvia Fontenete, Johan Christensen, Adriana Martinez-Silgado, Eduardo Zarzuela, Javier Muñoz, Diego Megias, Donatello Castellana, Robert Loewe, View ORCID ProfileMirna Perez-Moreno
doi: https://doi.org/10.1101/2020.07.17.209338
Silvia Fontenete
1Epithelial Cell Biology Group. Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, 2100, Denmark
2Epithelial Cell Biology Group, Cancer Cell Biology Programme, Spanish Cancer Research Centre (CNIO), Madrid, 28029, Spain
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Johan Christensen
2Epithelial Cell Biology Group, Cancer Cell Biology Programme, Spanish Cancer Research Centre (CNIO), Madrid, 28029, Spain
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Adriana Martinez-Silgado
1Epithelial Cell Biology Group. Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, 2100, Denmark
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Eduardo Zarzuela
3Proteomics Core Unit, Biotechnology Programme, CNIO, Madrid, 28029, Spain
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Javier Muñoz
3Proteomics Core Unit, Biotechnology Programme, CNIO, Madrid, 28029, Spain
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Diego Megias
4Confocal Microscopy Core Unit, Biotechnology Programme, CNIO, Madrid, 28029, Spain
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Donatello Castellana
5Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
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Robert Loewe
6Department of Dermatology, Medical University of Vienna, Vienna, 1090, Austria
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Mirna Perez-Moreno
1Epithelial Cell Biology Group. Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, 2100, Denmark
2Epithelial Cell Biology Group, Cancer Cell Biology Programme, Spanish Cancer Research Centre (CNIO), Madrid, 28029, Spain
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  • ORCID record for Mirna Perez-Moreno
  • For correspondence: mirna.pmoreno@bio.ku.dk
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Abstract

Skin tumor-initiating stem cells (tSCs) fuel skin squamous cell carcinoma (SCC) formation and development in a complex tumor microenvironment, but a role for immune cells in the tSC niche governing the process of tumor formation has remained elusive. Here, we define the existence of a tSC-macrophage niche, expressing high levels of Wnt ligands. Using conditional mouse genetic models to abrogate the secretion of Wnts, we show that both hair follicle SC- and macrophage-derived Wnts are essential for driving skin tumorigenesis, tSCs maintenance, and counteracting tumor regression. Loss of Wnts in either population uncouples the tSC-macrophage association. The proteomic signature of SCC cells reveals CD99 as a Wnt-dependent receptor for the macrophagecancer cell interaction. These results establish a role for a macrophage-tSC niche in governing SCC initiation and maintenance, uncovering potential candidates for immunoprevention against SCC.

One Sentence Summary A macrophage-skin tumor-initiating cells bonding Wnt loop drives tumorigenesis.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Author correction: Figure Legends

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Posted July 18, 2020.
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Wnt-mediated interactions of tumor-initiating cells with a macrophage niche drive skin tumor formation
Silvia Fontenete, Johan Christensen, Adriana Martinez-Silgado, Eduardo Zarzuela, Javier Muñoz, Diego Megias, Donatello Castellana, Robert Loewe, Mirna Perez-Moreno
bioRxiv 2020.07.17.209338; doi: https://doi.org/10.1101/2020.07.17.209338
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Wnt-mediated interactions of tumor-initiating cells with a macrophage niche drive skin tumor formation
Silvia Fontenete, Johan Christensen, Adriana Martinez-Silgado, Eduardo Zarzuela, Javier Muñoz, Diego Megias, Donatello Castellana, Robert Loewe, Mirna Perez-Moreno
bioRxiv 2020.07.17.209338; doi: https://doi.org/10.1101/2020.07.17.209338

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