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1.
Nat Commun ; 12(1): 5056, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417458

RESUMO

Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::NrasQ61K; Cdkn2a-/- melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism.


Assuntos
Epigênese Genética , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fator de Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Animais , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Adesão Celular/genética , Linhagem Celular Tumoral , Linhagem da Célula , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 2/metabolismo , Histonas/metabolismo , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos Nus , Camundongos Transgênicos , Invasividade Neoplásica , Micrometástase de Neoplasia , Ligação Proteica , Carga Tumoral
2.
Stem Cells Transl Med ; 10(4): 522-533, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33258291

RESUMO

Melanoma is the deadliest of all skin cancers due to its high metastatic potential. In recent years, advances in targeted therapy and immunotherapy have contributed to a remarkable progress in the treatment of metastatic disease. However, intrinsic or acquired resistance to such therapies remains a major obstacle in melanoma treatment. Melanoma disease progression, beginning from tumor initiation and growth to acquisition of invasive phenotypes and metastatic spread and acquisition of treatment resistance, has been associated with cellular dedifferentiation and the hijacking of gene regulatory networks reminiscent of the neural crest (NC)-the developmental structure which gives rise to melanocytes and hence melanoma. This review summarizes the experimental evidence for the involvement of NC stem cell (NCSC)-like cell states during melanoma progression and addresses novel approaches to combat the emergence of stemness characteristics that have shown to be linked with aggressive disease outcome and drug resistance.

3.
Nat Commun ; 9(1): 314, 2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29358574

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.

4.
Nat Commun ; 8(1): 1988, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29215016

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 Xenoenxerto
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