Peripheral glia drive the initiation of cutaneous squamous cell carcinoma

Abstract

Although tumor innervation is known to promote cancer progression, underlying mechanisms remain poorly understood and have mostly been linked to axonal signaling. Here, we identify peripheral glia as critical drivers of cutaneous squamous cell carcinoma (cSCC), the second most common skin cancer in humans. Tumor-associated glial cells (TAGs) resemble embryonic Schwann cell lineage stages, are abundant in the stroma of premalignant lesions and established murine and human cSCC, and are essential for tumor formation. TAG activation in premalignant lesions is triggered by UV-induced anti-inflammatory macrophages, which in turn are polarized by TAGs into pro-tumorigenic FcεRIα⁺ macrophages, key components of the cSCC microenvironment. Consequently, TAG depletion reduces FcεRIα⁺ macrophages, cancer-associated fibroblasts, and epithelial-mesenchymal transition in keratinocytes, thereby impairing cSCC initiation by disrupting intercellular communication required for tumor development. As most solid tumors are innervated and harbor peripheral glia, our findings reveal TAGs as regulators of tumor initiation with potential relevance beyond skin cancer.

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BibTeX RIS

BibTeX

@article{micheli2026peripheral,
  title = {{Peripheral glia drive the initiation of cutaneous squamous cell carcinoma}},
  author = {Sofia Micheli and Adrian Salas-Bastos and Khanh Huỳnh and Virginia Cecconi and Isabel Kolm and Jelena Vasilevska and Julien Debbache and Peter F. Renz and Johanna Diener and Myriam Gwerder and Ravidu Nakandalage and Janine Stadler and Phil F. Cheng and Gaetana Restivo and Jürg Hafner and Ataman Sendoel and Maries van den Broek and Salome Stierli and Lukas Sommer},
  journal = {Nature Communications},
  year = {2026},
  month = oct,
  doi = {10.1038/s41467-026-78778-1},
  url = {https://www.nature.com/articles/s41467-026-78778-1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Peripheral glia drive the initiation of cutaneous squamous cell carcinoma
AU  - Sofia Micheli
AU  - Adrian Salas-Bastos
AU  - Khanh Huỳnh
AU  - Virginia Cecconi
AU  - Isabel Kolm
AU  - Jelena Vasilevska
AU  - Julien Debbache
AU  - Peter F. Renz
AU  - Johanna Diener
AU  - Myriam Gwerder
AU  - Ravidu Nakandalage
AU  - Janine Stadler
AU  - Phil F. Cheng
AU  - Gaetana Restivo
AU  - Jürg Hafner
AU  - Ataman Sendoel
AU  - Maries van den Broek
AU  - Salome Stierli
AU  - Lukas Sommer
PY  - 2026
DA  - 2026/10/20
JO  - Nature Communications
DO  - 10.1038/s41467-026-78778-1
UR  - https://www.nature.com/articles/s41467-026-78778-1
AB  - Although tumor innervation is known to promote cancer progression, underlying mechanisms remain poorly understood and have mostly been linked to axonal signaling. Here, we identify peripheral glia as critical drivers of cutaneous squamous cell carcinoma (cSCC), the second most common skin cancer in humans. Tumor-associated glial cells (TAGs) resemble embryonic Schwann cell lineage stages, are abundant in the stroma of premalignant lesions and established murine and human cSCC, and are essential for tumor formation. TAG activation in premalignant lesions is triggered by UV-induced anti-inflammatory macrophages, which in turn are polarized by TAGs into pro-tumorigenic FcεRIα⁺ macrophages, key components of the cSCC microenvironment. Consequently, TAG depletion reduces FcεRIα⁺ macrophages, cancer-associated fibroblasts, and epithelial-mesenchymal transition in keratinocytes, thereby impairing cSCC initiation by disrupting intercellular communication required for tumor development. As most solid tumors are innervated and harbor peripheral glia, our findings reveal TAGs as regulators of tumor initiation with potential relevance beyond skin cancer.
SN  - 2041-1723
ER  -

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