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


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.

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
Glia ; 67(11): 2203-2215, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31215712


How tissues are maintained over a lifetime and repaired following injury are fundamental questions in biology with a disruption to these processes underlying pathologies such as cancer and degenerative disorders. It is becoming increasingly clear that each tissue has a distinct mechanism to maintain homeostasis and respond to injury utilizing different types of stem/progenitor cell populations depending on the insult and/or with a contribution from more differentiated cells that are able to dedifferentiate to aid tissue regeneration. Peripheral nerves are highly quiescent yet show remarkable regenerative capabilities. Remarkably, there is no evidence for a classical stem cell population, rather all cell-types within the nerve are able to proliferate to produce new nerve tissue. Co-ordinating the regeneration of this tissue are Schwann cells (SCs), the main glial cells of the peripheral nervous system. SCs exist in architecturally stable structures that can persist for the lifetime of an animal, however, they are not postmitotic, in that following injury they are reprogrammed at high efficiency to a progenitor-like state, with these cells acting to orchestrate the nerve regeneration process. During nerve regeneration, SCs show little plasticity, maintaining their identity in the repaired tissue. However, once free of the nerve environment they appear to exhibit increased plasticity with reported roles in the repair of other tissues. In this review, we will discuss the mechanisms underlying the homeostasis and regeneration of peripheral nerves and how reprogrammed progenitor-like SCs have broader roles in the repair of other tissues with implications for pathologies such as cancer.

Plasticidade Celular/fisiologia , Homeostase/fisiologia , Regeneração Nervosa/fisiologia , Nervos Periféricos/fisiologia , Animais , Diferenciação Celular/fisiologia , Humanos , Plasticidade Neuronal , Nervos Periféricos/patologia , Células de Schwann/metabolismo
Development ; 145(24)2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30413560


Peripheral nerves are highly regenerative, in contrast to the poor regenerative capabilities of the central nervous system (CNS). Here, we show that adult peripheral nerve is a more quiescent tissue than the CNS, yet all cell types within a peripheral nerve proliferate efficiently following injury. Moreover, whereas oligodendrocytes are produced throughout life from a precursor pool, we find that the corresponding cell of the peripheral nervous system, the myelinating Schwann cell (mSC), does not turn over in the adult. However, following injury, all mSCs can dedifferentiate to the proliferating progenitor-like Schwann cells (SCs) that orchestrate the regenerative response. Lineage analysis shows that these newly migratory, progenitor-like cells redifferentiate to form new tissue at the injury site and maintain their lineage, but can switch to become a non-myelinating SC. In contrast, increased plasticity is observed during tumourigenesis. These findings show that peripheral nerves have a distinct mechanism for maintaining homeostasis and can regenerate without the need for an additional stem cell population.This article has an associated 'The people behind the papers' interview.

Sistema Nervoso Central/fisiologia , Homeostase , Regeneração Nervosa/fisiologia , Células-Tronco Neurais/citologia , Nervos Periféricos/fisiologia , Animais , Axônios/metabolismo , Carcinogênese/patologia , Proliferação de Células , Proteínas da Matriz Extracelular/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Bainha de Mielina/metabolismo , Células-Tronco Neurais/metabolismo , Plasticidade Neuronal , Nervos Periféricos/citologia , Nervos Periféricos/ultraestrutura , Células de Schwann/metabolismo