High Copy Number Variations Correlate with a Pro-Tumoral Microenvironment and Worse Prognosis in Acral Lentiginous Melanoma

de la Rosa, Inés; Sisó, Pol; Ríos, Christopher; Gracia, Judith; Cuevas, Dolors; Maiques, Oscar; Eritja, Núria; Soria, Xavier; Angel-Baldó, Joan; Gatius, Sonia; Sanchez-Moral, Lidia; Sarrias, Maria-Rosa; Matias-Guiu, Xavier; Martí, Rosa M.; Macià, Anna

doi:10.3390/ijms26094097

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Open AccessArticle

High Copy Number Variations Correlate with a Pro-Tumoral Microenvironment and Worse Prognosis in Acral Lentiginous Melanoma

by

Inés de la Rosa

¹,

Pol Sisó

¹

,

Christopher Ríos

¹

,

Judith Gracia

¹,

Dolors Cuevas

^1,2,3,

Oscar Maiques

^4,5

,

Núria Eritja

^1,3,

Xavier Soria

⁶,

Joan Angel-Baldó

⁶

,

Sonia Gatius

^1,2,3,

Lidia Sanchez-Moral

⁷

,

Maria-Rosa Sarrias

^7,8

,

Xavier Matias-Guiu

^1,2,3

,

Rosa M. Martí

^1,3,6,*,†

and

Anna Macià

^1,*,†

¹

Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain

²

Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain

³

Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain

⁴

Cytoskeleton and Cancer Metastasis Group, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SM2 5NG, UK

⁵

Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London EC1M 6BQ, UK

⁶

Department of Dermatology, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain

⁷

Innate Immunity Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain

⁸

Center for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), 28029 Madrid, Spain

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work as co-senior authors.

Int. J. Mol. Sci. 2025, 26(9), 4097; https://doi.org/10.3390/ijms26094097

Submission received: 19 March 2025 / Revised: 16 April 2025 / Accepted: 19 April 2025 / Published: 25 April 2025

(This article belongs to the Special Issue Skin Diseases: From Molecular Pathology to Novel Therapeutic Approaches)

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Abstract

Acral lentiginous melanoma (ALM) is a rare melanoma subtype primarily located in acral regions. However, ALMs exhibit a distinctive genetic profile characterized by a high number of copy number variations (CNVs) and limited point mutations. Late diagnosis and restricted therapeutic efficacy contribute to its poor prognosis. The secretome within the tumor microenvironment (TME) influences immune modulation and plays a vital role in melanoma progression. We aim to analyze the role of ALM secretome and CNVs profile with prognosis in primary ALM patients. Here, we demonstrated that high CNV burden (CNVsHigh) was associated with worse clinicopathological characteristics and poor prognosis. Furthermore, our study also revealed that conditioned media (CM) of CNVsHigh genetic profile ALM cell line was associated with pro-tumoral, pro-angiogenic, and immunosuppressive secretome profiles. In addition, CM of CNVsHigh cell lines in vitro promotes macrophage polarization to immunosuppressive phenotype. Moreover, we observed an increased presence of immunosuppressive tumor-associated macrophages (TAMs) at the invasive front (IF) of CNVsHigh ALM biopsies. This research reveals the adverse prognostic impact of CNVsHigh in ALM patients, establishing a novel link with a pro-tumor secretome, offering potential biomarkers for prognosis and personalized treatment to enhanced disease monitoring in ALM patients.

Keywords: acral lentiginous melanoma; copy number variation; tumor microenvironment; secretome; prognosis

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MDPI and ACS Style

de la Rosa, I.; Sisó, P.; Ríos, C.; Gracia, J.; Cuevas, D.; Maiques, O.; Eritja, N.; Soria, X.; Angel-Baldó, J.; Gatius, S.; et al. High Copy Number Variations Correlate with a Pro-Tumoral Microenvironment and Worse Prognosis in Acral Lentiginous Melanoma. Int. J. Mol. Sci. 2025, 26, 4097. https://doi.org/10.3390/ijms26094097

AMA Style

de la Rosa I, Sisó P, Ríos C, Gracia J, Cuevas D, Maiques O, Eritja N, Soria X, Angel-Baldó J, Gatius S, et al. High Copy Number Variations Correlate with a Pro-Tumoral Microenvironment and Worse Prognosis in Acral Lentiginous Melanoma. International Journal of Molecular Sciences. 2025; 26(9):4097. https://doi.org/10.3390/ijms26094097

Chicago/Turabian Style

de la Rosa, Inés, Pol Sisó, Christopher Ríos, Judith Gracia, Dolors Cuevas, Oscar Maiques, Núria Eritja, Xavier Soria, Joan Angel-Baldó, Sonia Gatius, and et al. 2025. "High Copy Number Variations Correlate with a Pro-Tumoral Microenvironment and Worse Prognosis in Acral Lentiginous Melanoma" International Journal of Molecular Sciences 26, no. 9: 4097. https://doi.org/10.3390/ijms26094097

APA Style

de la Rosa, I., Sisó, P., Ríos, C., Gracia, J., Cuevas, D., Maiques, O., Eritja, N., Soria, X., Angel-Baldó, J., Gatius, S., Sanchez-Moral, L., Sarrias, M.-R., Matias-Guiu, X., Martí, R. M., & Macià, A. (2025). High Copy Number Variations Correlate with a Pro-Tumoral Microenvironment and Worse Prognosis in Acral Lentiginous Melanoma. International Journal of Molecular Sciences, 26(9), 4097. https://doi.org/10.3390/ijms26094097

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High Copy Number Variations Correlate with a Pro-Tumoral Microenvironment and Worse Prognosis in Acral Lentiginous Melanoma

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