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

Authors :
Matilde Monti
Luisa Benerini Gatta
Mattia Bugatti
Irene Pezzali
Sara Picinoli
Marcello Manfredi
Antonio Lavazza
Virginia Vita Vanella
Veronica De Giorgis
Lucia Zanatta
Francesco Missale
Silvia Lonardi
Benedetta Zanetti
Giovanni Bozzoni
Moris Cadei
Andrea Abate
Barbara Vergani
Piera Balzarini
Simonetta Battocchio
Carla Facco
Mario Turri-Zanoni
Paolo Castelnuovo
Piero Nicolai
Ester Fonsatti
Biagio Eugenio Leone
Emilio Marengo
Sandra Sigala
Roberto Ronca
Michela Perego
Davide Lombardi
William Vermi
Source :
Journal of Translational Medicine, Vol 22, Iss 1, Pp 1-24 (2024)
Publication Year :
2024
Publisher :
BMC, 2024.

Abstract

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 relevance, 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 proteomic analysis of SN-MM cell lines revealed that RICTOR, a subunit of mTORC2 complex, is the most significantly activated upstream regulator, suggesting a relevant role for the PI3K-Akt-mTOR pathway in these neoplasms. Consistently, phosphorylation of NDRG1 and Akt activation was observed in SN-MM, the latter being constitutive and sustained by PTEN loss in SN-MM2 and SN-MM3. The cell viability impairment induced by LY294002 confirmed a functional role for the PI3K-Akt-mTOR pathway in SN-MM cell lines. Conclusions Overall, these novel and unique cellular systems represent relevant experimental tools for a better understanding of the biology of these neoplasms and, as an extension, to MM from other sites.

Details

Language :
English
ISSN :
14795876
Volume :
22
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Journal of Translational Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.735a9e3b74ed45228ece9b45b07e75d1
Document Type :
article
Full Text :
https://doi.org/10.1186/s12967-023-04784-2