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1.
Nat Commun ; 12(1): 5041, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413299

RESUMO

In vivo reprogramming provokes a wide range of cell fate conversion. Here, we discover that in vivo induction of higher levels of OSKM in mouse somatic cells leads to increased expression of primordial germ cell (PGC)-related genes and provokes genome-wide erasure of genomic imprinting, which takes place exclusively in PGCs. Moreover, the in vivo OSKM reprogramming results in development of cancer that resembles human germ cell tumors. Like a subgroup of germ cell tumors, propagated tumor cells can differentiate into trophoblasts. Moreover, these tumor cells give rise to induced pluripotent stem cells (iPSCs) with expanded differentiation potential into trophoblasts. Remarkably, the tumor-derived iPSCs are able to contribute to non-neoplastic somatic cells in adult mice. Mechanistically, DMRT1, which is expressed in PGCs, drives the reprogramming and propagation of the tumor cells in vivo. Furthermore, the DMRT1-related epigenetic landscape is associated with trophoblast competence of the reprogrammed cells and provides a therapeutic target for germ cell tumors. These results reveal an unappreciated route for somatic cell reprogramming and underscore the impact of reprogramming in development of germ cell tumors.


Assuntos
Células-Tronco Pluripotentes Induzidas/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias/patologia , Fatores de Transcrição/metabolismo , Animais , Animais Geneticamente Modificados , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Células Cultivadas , Reprogramação Celular/fisiologia , Epigênese Genética , Feminino , Impressão Genômica , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Fatores de Transcrição/genética
2.
Cell Rep ; 34(8): 108772, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33626352

RESUMO

Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking, and IPNB pathogenesis remains unclear. Here, we use a doxycycline-inducible tetracycline (Tet)-on mice model to control fibroblast growth factor 10 (FGF10) expression, which regulates branching and tubule formation. FGF10-induced IPNB mimics the multifocal and divergent human IPNB phenotypes via the FGF10-FGF receptor 2 (FGFR2)-RAS-extracellular-signal-regulated kinase (ERK) signaling pathway. A paracrine/autocrine growth factor is sufficient to initiate and maintain IPNB originating from the peribiliary glands, including biliary stem/progenitor cells. With KrasG12D, p53, or p16 mutations or both, Fgf10-induced IPNB shows stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes and progression are suppressed by the inhibition of the FGF10-FGFR2-RAS-ERK signaling pathway, demonstrating that the signal is a therapeutic target for IPNB and associated carcinoma.


Assuntos
Neoplasias dos Ductos Biliares/enzimologia , Carcinoma Papilar/enzimologia , Colangiocarcinoma/enzimologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fator 10 de Crescimento de Fibroblastos/metabolismo , Células-Tronco Neoplásicas/enzimologia , Lesões Pré-Cancerosas/enzimologia , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Carcinoma Papilar/tratamento farmacológico , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Células Cultivadas , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Progressão da Doença , Feminino , Fator 10 de Crescimento de Fibroblastos/genética , Regulação Neoplásica da Expressão Gênica , Genes ras , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Células-Tronco Neoplásicas/patologia , Fosforilação , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Inibidores de Proteínas Quinases/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais
3.
Biochem Biophys Res Commun ; 455(1-2): 10-5, 2014 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-25019993

RESUMO

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by the transient expression of reprogramming factors. During the reprogramming process, somatic cells acquire the ability to undergo unlimited proliferation, which is also an important characteristic of cancer cells, while their underlying DNA sequence remains unchanged. Based on the characteristics shared between pluripotent stem cells and cancer cells, the potential involvement of the factors leading to reprogramming toward pluripotency in cancer development has been discussed. Recent in vivo reprogramming studies provided some clues to understanding the role of reprogramming-related epigenetic regulation in cancer development. It was shown that premature termination of the in vivo reprogramming result in the development of tumors that resemble pediatric cancers. Given that epigenetic modifications play a central role during reprogramming, failed reprogramming-associated cancer development may have provided a proof of concept for epigenetics-driven cancer development in vivo.


Assuntos
Reprogramação Celular , Epigênese Genética , Neoplasias/genética , Células-Tronco Pluripotentes Induzidas/metabolismo
4.
Cell ; 156(4): 663-77, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24529372

RESUMO

Cancer is believed to arise primarily through accumulation of genetic mutations. Although induced pluripotent stem cell (iPSC) generation does not require changes in genomic sequence, iPSCs acquire unlimited growth potential, a characteristic shared with cancer cells. Here, we describe a murine system in which reprogramming factor expression in vivo can be controlled temporally with doxycycline (Dox). Notably, transient expression of reprogramming factors in vivo results in tumor development in various tissues consisting of undifferentiated dysplastic cells exhibiting global changes in DNA methylation patterns. The Dox-withdrawn tumors arising in the kidney share a number of characteristics with Wilms tumor, a common pediatric kidney cancer. We also demonstrate that iPSCs derived from Dox-withdrawn kidney tumor cells give rise to nonneoplastic kidney cells in mice, proving that they have not undergone irreversible genetic transformation. These findings suggest that epigenetic regulation associated with iPSC derivation may drive development of particular types of cancer.


Assuntos
Reprogramação Celular , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/patologia , Animais , Metilação de DNA , Doxiciclina/farmacologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Neoplasias Renais/induzido quimicamente , Camundongos , Camundongos Transgênicos , Fatores de Transcrição/metabolismo
5.
Int J Cancer ; 132(6): 1240-8, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23180619

RESUMO

Cancer develops through the accumulation of genetic and epigenetic abnormalities. The role of genetic alterations in cancer development has been demonstrated by reverse genetic approaches. However, evidence indicating the functional significance of epigenetic abnormalities remains limited due to the lack of means to actively modify coordinated epigenetic regulations in the genome. Application of the reprogramming technology may help researchers to overcome this limitation and shed new light on cancer research. Reprogramming is accompanied by dynamic changes of epigenetic modifications and is therefore considered to be a useful tool to induce global epigenetic changes in cancer genomes. We herein discuss the similarities between reprogramming processes and carcinogenesis and propose the potential use of reprogramming technology to help understanding of the significance of epigenetic regulations in cancer cells. We, also discuss the application of induced pluripotent stem cell technology to cancer modeling based on the similar characteristics between pluripotent stem cells and cancer cells.


Assuntos
Reprogramação Celular/genética , Epigênese Genética , Neoplasias/genética , Neoplasias/patologia , Animais , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste , Genes ras , Impressão Genômica , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Células-Tronco Pluripotentes Induzidas/transplante , Neoplasias/etiologia , Neoplasias/terapia , Complexo Repressor Polycomb 2/fisiologia
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