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1.
Theranostics ; 11(16): 7671-7684, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335957

RESUMO

Snail1 is a transcriptional factor required for epithelial to mesenchymal transition and activation of cancer-associated fibroblasts (CAF). Apart from that, tumor endothelial cells also express Snail1. Here, we have unraveled the role of Snail1 in this tissue in a tumorigenic context. Methods: We generated transgenic mice with an endothelial-specific and inducible Snail1 depletion. This murine line was crossed with MMTV-PyMT mice that develop mammary gland tumors and the consequence of Snail1 depletion in the endothelium were investigated. We also interfere Snail1 expression in cultured endothelial cells. Results: Specific Snail1 depletion in the endothelium of adult mice does not promote an overt phenotype; however, it delays the formation of mammary gland tumors in MMTV-PyMT mice. These effects are associated to the inability of Snail1-deficient endothelial cells to undergo angiogenesis and to enhance CAF activation in a paracrine manner. Moreover, tumors generated in mice with endothelium-specific Snail1 depletion are less advanced and show a papillary phenotype. Similar changes on onset and tumor morphology are observed by pretreatment of MMTV-PyMT mice with the angiogenic inhibitor Bevacizumab. Human breast papillary carcinomas exhibit a lower angiogenesis and present lower staining of Snail1, both in endothelial and stromal cells, compared with other breast neoplasms. Furthermore, human breast tumors datasets show a strong correlation between Snail1 expression and high angiogenesis. Conclusion: These findings show a novel role for Snail1 in endothelial cell activation and demonstrate that these cells impact not only on angiogenesis, but also on tumor onset and phenotype.


Assuntos
Neoplasias da Mama/genética , Fatores de Transcrição da Família Snail/metabolismo , Animais , Neoplasias da Mama/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Fibroblastos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neovascularização Patológica/patologia , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição/metabolismo
2.
Gut ; 68(2): 322-334, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29650531

RESUMO

OBJECTIVES: CTNNB1-mutated hepatocellular carcinomas (HCCs) constitute a major part of human HCC and are largely inaccessible to target therapy. Yet, little is known about the metabolic reprogramming induced by ß-catenin oncogenic activation in the liver. We aimed to decipher such reprogramming and assess whether it may represent a new avenue for targeted therapy of CTNNB1-mutated HCC. DESIGN: We used mice with hepatocyte-specific oncogenic activation of ß-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of Pparα in knock-out mice and analysed the consequences of fatty acid oxidation (FAO) using etomoxir. We explored the expression of the FAO pathway in an annotated human HCC dataset. RESULTS: ß-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that Pparα is a ß-catenin target involved in FAO metabolic reprograming. Deletion of Pparα was sufficient to block the initiation and progression of ß-catenin-dependent HCC development. FAO was also enriched in human CTNNB1-mutated HCC, under the control of the transcription factor PPARα. CONCLUSIONS: FAO induced by ß-catenin oncogenic activation in the liver is the driving force of the ß-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for CTNNB1-mutated HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Ácidos Graxos/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , beta Catenina/metabolismo , Animais , Compostos de Epóxi/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Knockout , Mutação , Oxirredução , PPAR alfa/fisiologia , beta Catenina/genética
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