Novel cellular systems unveil mucosal melanoma initiating cells and a role for PI3K/ Akt/mTOR pathway in mucosal melanoma fitness

Sep 21, 2026

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Mucosal melanomas are highly aggressive neoplasms with limited benefit from existing therapies, compounded by a lack of pre-clinical cellular systems that constrains understanding of their immunobiology. Five patient-derived sino-nasal mucosa cell lines (SN-MM1-5) were generated and validated by electron microscopy, immunohistochemistry, proteomic profiling, and in vivo tumorigenicity in NOD/SCID mice. Xenografts revealed melanoma-initiating cell clusters, while LY294002 and cisplatin sensitivity highlighted pathway-dependent fitness.

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CategoryHealthcare

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Abstract

Background

Methods

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Background

Monti etal. Journal of Translational Medicine (2024) 22:35 [https://doi.org/10.1186/s12967-023-04784-2](https://doi.org/10.1186/s12967-023-04784-2) Journal of Translational Medicine RESEARCH Open Access Novel cellular systems unveil mucosal melanoma initiating cells and a role for PI3K/ Akt/mTOR pathway in mucosal melanoma fitness Matilde Monti1†, Luisa Benerini Gatta1,2†, Mattia Bugatti 1, Irene Pezzali 1, Sara Picinoli 1, Marcello Manfredi3,4, Antonio Lavazza5, Virginia Vita Vanella3,4, Veronica De Giorgis3,4, Lucia Zanatta6, Francesco Missale1,7, Silvia Lonardi 1, Benedetta Zanetti1, Giovanni Bozzoni5, Moris Cadei1, Andrea Abate1, Barbara Vergani8, Piera Balzarini 1, Simonetta Battocchio9, Carla Facco 10, Mario Turri‑Zanoni11, Paolo Castelnuovo11, Piero Nicolai 12, Ester Fonsatti13, Biagio Eugenio Leone8, Emilio Marengo14, Sandra Sigala1, Roberto Ronca 1, Michela Perego 15, Davide Lombardi16† and William Vermi1,17,18* Abstract Background Mucosal Melanomas (MM) are highly aggressive neoplasms arising from mucosal melanocytes. Current treatments offer a limited survival benefit for patients with advanced MM; moreover, the lack of pre‑clinical cellular systems has significantly limited the understanding of their immunobiology. Methods Five novel cell lines were obtained from patient‑derived biopsies of MM arising in the sino‑nasal mucosa and designated as SN‑MM1‑5. The morphology, ultrastructure and melanocytic identity of SN‑MM cell lines were validated by transmission electron microscopy and immunohistochemistry. Moreover, in vivo tumorigenicity of SN‑MM1‑5 was tested by subcutaneous injection in NOD/SCID mice. Molecular characterization of SN‑MM cell lines was performed by a mass‑spectrometry proteomic approach, and their sensitivity to PI3K chemical inhibitor LY294002 was validated by Akt activation, measured by pAkt(Ser473) and pAkt(Thr308) in immunoblots, and MTS assay. Results This study reports the validation and functional characterization of five newly generated SN‑MM cell lines. Compared to the normal counterpart, the proteomic profile of SN‑MM is consistent with transformed melanocytes showing a heterogeneous degree of melanocytic differentiation and activation of cancer‑related pathways. All SN‑MM cell lines resulted tumorigenic in vivo and display recurrent structural variants according to aCGH analysis. Of rel‑ evance, the microscopic analysis of the corresponding xenotransplants allowed the identification of clusters of MITF‑/ CDH1‑/CDH2 + /ZEB1+ /CD271 + cells, supporting the existence of melanoma‑initiating cells also in MM, as confirmed in clinical samples. In vitro, SN‑MM cell lines were sensitive to cisplatin, but not to temozolomide. Moreover, the pro‑ teomic analysis of SN‑MM cell lines revealed that RICTOR, a subunit of mTORC2 complex, is the most significantly †Matilde Monti, Luisa Benerini Gatta and Davide Lombardi have equally contributed to this work. *Correspondence: William Vermi [william.vermi@unibs.it](william.vermi@unibs.it) Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creat

FAQs

What cellular systems were developed in this study?

Five novel cell lines, SN-MM1-5, were obtained from patient-derived sino-nasal mucosal melanoma biopsies and designated as new mucosal melanoma model systems.

How were the new SN-MM cell lines validated and tested?

Their morphology and melanocytic identity were validated using transmission electron microscopy and immunohistochemistry. Tumorigenicity was tested in NOD/SCID mice, and molecular characterization used mass-spectrometry proteomics.

What did the study find about melanoma-initiating cells and drug sensitivity?

Microscopic analysis of xenotransplants identified clusters consistent with melanoma-initiating cells, and the SN-MM cell lines were sensitive to cisplatin but not temozolomide, with LY294002 implicating PI3K-AKT-mTOR pathway fitness.

Sep 21, 2026

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