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

Fontenete, S.; Christensen, J. R.; Martinez-Silgado, A.; Zarzuela, E.; Munoz, J.; Megias, D.; Castellana, D.; Loewe, R.; Perez-Moreno, M.

doi:10.1101/2020.07.17.209338

bioRxiv · 10.1101/2020.07.17.209338

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

Fontenete, S.·Christensen, J. R.·Martinez-Silgado, A.·Zarzuela, E.·Munoz, J.·Megias, D.·Castellana, D.·Loewe, R.·Perez-Moreno, M.

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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 SummaryA macrophage-skin tumor-initiating cells bonding Wnt loop drives tumorigenesis.

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Fontenete, S., Christensen, J. R., Martinez-Silgado, A., Zarzuela, E., Munoz, J., Megias, D., Castellana, D., Loewe, R., Perez-Moreno, M.. 2020-07-17. Wnt-mediated interactions of tumor-initiating cells with a macrophage niche drive skin tumor formation. https://doi.org/10.1101/2020.07.17.209338

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