Schwann cell plasticity regulates melanoma growth and responses to immunotherapy

• Autores: Francisco Gracia Quiles
• Directores de la Tesis: Berta López Sánchez-Laorden (dir. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2026
• Idioma: inglés
• Tribunal Calificador de la Tesis: María Dolores Mayán Santos (presid.), Francisco José Taberner Sanchis (secret.), Juan Rodríguez Vita (voc.)
• Programa de doctorado: Programa Oficial de Doctorado en Neurociencias
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• Resumen

  • Melanoma is an aggressive form of skin cancer whose progression and therapeutic response are strongly influenced by its highly heterogeneous tumour microenvironment (TME). While several stromal components have been extensively studied in melanoma, the contribution of the peripheral nervous system (PNS) remains comparatively unexplored. Schwann cells (SCs), the glial cells of peripheral nerves, are essential for nerve maintenance and regeneration and are characterized by a remarkable degree of phenotypic plasticity. In response to injury, SCs undergo extensive transcriptional reprogramming to acquire repair-promoting phenotypes. However, how this intrinsic plasticity is hijacked by tumours and contributes to melanoma progression is poorly understood.

    In this thesis, we investigate the role of SCs in melanoma, focusing on the EMT transcription factor (EMT-TF) Prrx1 as a central regulator of SC plasticity. By combining lineage tracing, single-cell transcriptomics, genetically engineered mouse models, and in vivo melanoma and metastasis assays, we characterize the presence, heterogeneity and activation of SCs within the melanoma microenvironment. We show that melanoma-associated SCs acquire activated, repair-like phenotypes and identify Prrx1 as a key transcriptional regulator acting upstream of Jun to restrain SC activation across both regenerative and tumour contexts. Depletion of Prrx1 in SCs drives a hyperactivated repair-like state that enhances their pro-tumorigenic potential and alters SCs functional heterogeneity, including a reduction in inflammatory SCs populations. Consequently, tumours exhibit a more immunosuppressive microenvironment and reduced infiltration of cytotoxic immune cells, leading to enhanced tumour growth and increased metastatic burden. Consistent with this, Prrx1-dependent SCs states critically influence therapeutic outcome, as loss of Prrx1 impairs the efficacy of anti–PD-L1 immunotherapy in melanoma. Together, these findings identify SCs as active orchestrators of melanoma progression and tumour–immune interactions and position Prrx1 as a central regulator of SC plasticity. This work provides a framework for understanding how glial reprogramming contributes to melanoma biology and opens new avenues for targeting neural–tumour crosstalk to improve therapeutic strategies in advanced melanoma.