A novel patient-derived cutaneous melanoma cell line reveals key features of metastatic melanoma

Ana Tomás^1,2Lúcia Roque¹Inês Francisco¹Ana Silva¹Hugo Nunes³Emanuel Gouveia³Elisabete Lopez Carvalho⁴Victor Farricha⁵Cecília Moura⁶Joaninha Costa Rosa⁷Pedro Garrido⁶Cristina Albuquerque¹M Guadalupe Cabral²Patrícia Matos Pereira³Marta Pojo^1*

• ¹Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
• ²NOVA Medical School, NOVA University of Lisbon, Lisbon, Portugal
• ³Serviço de Oncologia Médica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
• ⁴Unidade de Investigação Clínica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
• ⁵Serviço de Cirurgia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
• ⁶Serviço de Dermatologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
• ⁷Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal

Cutaneous melanoma (CM) is an aggressive form of skin cancer, with rising incidence and poor prognosis at advanced stages. While early-stage CM typically carries a favorable prognosis, a small subset of patients relapses and progresses to advanced disease, highlighting the need for a deeper understanding of CM biology. Here, we describe the establishment and characterization of a novel patient-derived primary cell line, MelT79, developed from a metastatic lesion of a patient initially diagnosed with stage IB CM, which unexpectedly progressed to advanced disease.MelT79 exhibits a complex karyotype with significant chromosomal alterations, including deletions affecting key genes such as CDKN2A/B, SPRED1, and B2M, implicated in melanomagenesis and therapy resistance. Additionally, MelT79 harbors both the BRAF V600E mutation and a rare RET S649L mutation, which has not been previously reported in CM. RET S649L was also identified in an earlier metastatic lesion, possibly conferring a selective advantage, and highlighting this mutation as a potential therapeutic target. Phenotypically, MelT79 displays both differentiation and invasive traits, suggesting that its heterogeneity might contribute to progression and therapy resistance. Furthermore, the cell line exhibited moderate sensitivity to BRAF and MEK inhibitors when compared to other commercially available cell lines, reflecting its heterogeneity.MelT79 represents a valuable model for understanding CM heterogeneity, progression, and resistance mechanisms, offering new avenues for novel therapeutic interventions in CM.