RESUMO
The originally published version of this Article was updated shortly after publication to add the words 'The' and 'affinity' to the title, following their inadvertent removal during the production process. This has now been corrected in both the PDF and HTML versions of the Article.
RESUMO
Cutaneous melanoma represents the most fatal skin cancer due to its high metastatic capacity. According to the "phenotype switching" model, the aggressive nature of melanoma cells results from their intrinsic potential to dynamically switch from a high-proliferative/low-invasive to a low-proliferative/high-invasive state. Here we identify the low affinity neurotrophin receptor CD271 as a key effector of phenotype switching in melanoma. CD271 plays a dual role in this process by decreasing proliferation, while simultaneously promoting invasiveness. Dynamic modification of CD271 expression allows tumor cells to grow at low levels of CD271, to reduce growth and invade when CD271 expression is high, and to re-expand at a distant site upon decrease of CD271 expression. Mechanistically, the cleaved intracellular domain of CD271 controls proliferation, while the interaction of CD271 with the neurotrophin receptor Trk-A modulates cell adhesiveness through dynamic regulation of a set of cholesterol synthesis genes relevant for patient survival.
Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/patologia , Proteínas do Tecido Nervoso/metabolismo , Receptor trkA/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Neoplasias Cutâneas/patologia , Animais , Adesão Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Fibroblastos , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Queratinócitos , Masculino , Melanoma/genética , Melanoma/mortalidade , Camundongos , Camundongos Nus , Invasividade Neoplásica/patologia , Domínios Proteicos , RNA Interferente Pequeno/metabolismo , Receptor trkA/genética , Pele/citologia , Pele/patologia , Técnicas de Cultura de Tecidos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
To overcome the lack of effective therapeutics for aggressive melanoma, new research models closely resembling the human disease are required. Here we report the development of a fully orthotopic, humanized in vivo model for melanoma, faithfully recapitulating human disease initiation and progression. To this end, human melanoma cells were seeded into engineered human dermo-epidermal skin substitutes. Transplantation onto the back of immunocompromised rats consistently resulted in the development of melanoma, displaying the hallmarks of their parental tumors. Importantly, all initial steps of disease progression were recapitulated, including the incorporation of the tumor cells into their physiological microenvironment, transition of radial to vertical growth, and establishment of highly vascularized, aggressive tumors with dermal involvement. Because all cellular components can be individually accessed using this approach, it allows manipulation of the tumor cells, as well as of the keratinocyte and stromal cell populations. Therefore, in one defined model system, tumor cell-autonomous and non-autonomous pathways regulating human disease progression can be investigated in a humanized, clinically relevant context.