Angélique Gougelet - Academia.edu (original) (raw)
Papers by Angélique Gougelet
Molecular therapy, Apr 1, 2024
Journal of translational medicine, Apr 8, 2024
Methods in molecular biology, 2024
HAL (Le Centre pour la Communication Scientifique Directe), Oct 18, 2013
Les microARN (miARN) sont de petits ARN non-codants contrôlant négativement l'expression de leurs... more Les microARN (miARN) sont de petits ARN non-codants contrôlant négativement l'expression de leurs cibles. Par leur mutiplicité d'action, ils jouent un rôle majeur dans nombre de processi physiologiques et dans la tumorigenèse. L'identification de signatures miARN pour une grande variété de tumeurs, dont les carcinomes hépatocellulaires (CHC), ont mis en évidence le rôle ambivalent des miARN, à la fois oncogène et suppresseur de tumeurs. Dans cette revue, nous faisons un tour d'horizon des connaissances actuelles au sujet de la dérégulation des miARN dans les maladies du foie. Toutes les études dédiées aux miARN sont en faveur de leur utilisation en tant qu'outil diagnostique, pronostique et thérapeutique. Un intérêt tout particulier sera porté aux stratégies thérapeutiques qui ciblent les miARN dans le CHC.
Journal of Steroid Biochemistry and Molecular Biology, 2005
M S-medecine Sciences, Oct 1, 2013
Journal of Hepatology, Apr 1, 2018
to 1 year). Conclusion: This is the first report highlighting the essential role of RuvBL1 for he... more to 1 year). Conclusion: This is the first report highlighting the essential role of RuvBL1 for hepatocyte survival and the impact of its loss on liver carcinogenesis. The increased HCC incidence does not reflect a tumor-suppressor role of RuvBL1, rather, it is the outcome of a chronic regenerative process from staminal precursors. This model may prove useful to investigate the mechanism underlying liver regeneration in the context of chronic hepatic damage.
Le ligand, le promoteur et la lignee cellulaire influencent les capacites transactivatrices des r... more Le ligand, le promoteur et la lignee cellulaire influencent les capacites transactivatrices des recepteurs aux œstrogenes (ER) a et b. Le contexte cellulaire (expression/acetylation de ER/des coregulateurs) module l’activite suppressive de ERb, dependante de son AF1, envers ERa. Trois approches anticancereuses ont ete testees : l’anti-œstrogene pur RU 58668 induit la degradation proteasomale de ERa, reduit sa capacite de transactivation mais affecte peu ERb, facteur de bon pronostic. Les inhibiteurs d’histone-deacetylases, agents pro-apoptotiques et cytostatiques, provoquent la degradation de ERa mais stabilisent ERb. L’association de ces deux agents anticancereux augmente les effets antiproliferatifs et proapoptotiques observes sur des cellules MCF-7 ERa+ERb+ avec ces molecules seules. Enfin, les inhibiteurs de la hsp90, chaperon de ER, provoquent sa degradation proteasomale, inhibent son activite transcriptionnelle, induisent l’apoptose des cellules et bloquent leur proliferation.
Journal of Hepatology, 2022
BACKGROUND AND AIMS One-third of hepatocellular carcinomas (HCCs) harbor mutations activating the... more BACKGROUND AND AIMS One-third of hepatocellular carcinomas (HCCs) harbor mutations activating the β-catenin pathway predominantly via mutations in CTNNB1 gene itself. Mouse models of Apc loss-of-function are widely used to mimic β-catenin-dependent tumorigenesis. Given the low prevalence of APC mutations in human HCCs we aimed to generate liver tumors through CTNNB1 exon 3 deletion (βcatΔex3). We then compared βcatΔex3 liver tumors with liver tumors generated via frameshift in exon 15 of Apc (Apcfs-ex15). METHODS We used hepatocyte-specific and inducible mouse models generated through either a Cre-Lox or a CRISPR/Cas9 approach using AAV vectors. Tumors generated by the Cre-Lox models were phenotypically analyzed using immunohistochemistry and were selected for transcriptomic analysis by RNA-sequencing. Mouse RNAseq data were compared to human RNAseq data (8 normal tissues, 48 HCCs, 9 hepatoblastomas) in an integrative analysis. Tumors generated via CRISPR were analyzed using DNA sequencing and immunohistochemistry. RESULTS Mice with CTNNB1 exon 3 deletion in hepatocytes developed liver tumors indistinguishable from Apcfs-ex15 liver tumors. Both Apcfs-ex15 and βcatΔex3 mouse models induced growth of two phenotypically distinct tumors (differentiated or undifferentiated). Integrative analysis of human and mouse tumors showed that differentiated mouse tumors cluster with well-differentiated human CTNNB1-mutated tumors. Conversely, undifferentiated mouse tumors cluster with human mesenchymal hepatoblastomas and harbor activated YAP signaling. CONCLUSION Apcfs-ex15 and βcatΔex3 mouse models both induce growth of tumors that are transcriptionally similar to either well-differentiated and β-catenin-activated human HCCs or mesenchymal hepatoblastomas. LAY SUMMARY New and easy-to-use transgenic mouse models of liver primary cancers have been generated, with mutations in the gene coding beta-catenin, frequent in both adult and pediatric liver primary cancers. The mice develop both types of cancer, constituting a strong preclinical model.
Gut, 2019
Liver cancer is the second leading cause of cancer-related deaths worldwide, for which therapeuti... more Liver cancer is the second leading cause of cancer-related deaths worldwide, for which therapeutic options are very limited and novel strategies alarmingly needed. The leading risk factor for hepatocellular carcinoma (HCC) is cirrhosis due to HBV and HCV viruses, alcohol abuse, genotoxic exposure and metabolic disorders increasingly associated with diabetes and obesity. HCC is the paradigm of inflammation-associated cancer, with >80% of HCC emerging consecutively to a vast remodelling of liver stroma. To restrain inflammatory response, liver parenchyma physiologically harbours a specific microenvironment to prevent the establishment of inflammation. Immune cells largely orchestrate liver protection, in particular Kupffer cells, the liver macrophages, in partnership with fibroblasts. Nevertheless, when it gets into chronicity, liver inflammation sensitises to cancer development, tumor-associated stroma being recognised as a major hallmark of cancer, as described by Hanahan and Weinberg in 2011.1 During hepatocyte transformation, the surrounding cells, including cancer-associated fibroblasts, hepatic stellate cells, tumour-infiltrating leukocytes and tumour-associated macrophages (TAM) are abnormally activated and/or recruited. These cells secrete a cocktail of growth factors, cytokines and chemokines, which exacerbate liver inflammation and injury in favour of hepatocarcinogenesis.2 Macrophages are the major part of immune cell infiltrates in solid tumours, and the density of macrophages is strongly correlated to poor overall survival, including in HCC. Inversely, myeloid-derived suppressor cells (MDSCs) have emerged as central …
Gut, Jun 19, 2015
Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third o... more Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third of these tumours presents activating mutations of the β-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high, and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by β-catenin, potentially involved in liver tumorigenesis. We used a mouse model, in which β-catenin signalling was overactivated exclusively in the liver by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumours with properties similar to human HCC. We found that miR-34a was regulated by β-catenin, and significantly induced by the overactivation of β-catenin signalling in mouse tumours and in patients with HCC. An inhibitor of miR-34a (locked nucleic acid, LNA-34a) exerted antiproliferative activity in primary cultures of hepatocyte. This inhibition of p...
Copyright © 2011 Angélique Gougelet et al. This is an open access article distributed under the C... more Copyright © 2011 Angélique Gougelet et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Sarcomas are divided into a group with specific alterations and a second presenting a complex karyotype, sometimes difficult to diagnose or with few therapeutic options available. We assessed if miRNA profiling by TaqMan low density arrays could predict the response of undifferentiated rhabdomyosarcoma (RMS) and osteosarcoma to treatment. We showed that miRNA signatures in response to a therapeutic agent (chemotherapy or the mTOR inhibitor RAD-001) were cell and drug specific on cell lines and a rat osteosarcoma model. This miRNA signature was related to cell or tumour sensitivity to this treatment and might be not due to chromosomal aberrations, as revealed by a CGH array analysis of rat tumours. Strikingly, miRNA profiling gave...
![Research paper thumbnail of [Metabolic imaging assessing choline addiction in liver primary cancers predicts their oncogenotype and opens a new therapeutic avenue]](https://attachments.academia-assets.com/78283406/thumbnails/1.jpg)
](Medecine sciences : M/S, 2020
Vers une imagerie métabolique des tumeurs cancéreuses L'imagerie des tumeurs malignes par tomogra... more Vers une imagerie métabolique des tumeurs cancéreuses L'imagerie des tumeurs malignes par tomographie par émission de positons (TEP) utilise une propriété essentielle des cellules cancéreuses : leur métabolisme modifié afin d'acquérir une autonomie énergétique. Suite à l'injection d'un métabolite radio-marqué, la tumeur primaire et ses métastases éventuelles sont visualisées par l'incorporation accrue de ce métabolite dans les cellules tumorales par rapport aux cellules saines adjacentes [1] (➜). L'utilisation de cette technique d'imagerie dans le cancer a fait suite aux travaux
Background and aims One-third of hepatocellular carcinomas (HCCs) have mutations that activate th... more Background and aims One-third of hepatocellular carcinomas (HCCs) have mutations that activate the β-catenin pathway with mostly CTNNB1 mutations. Mouse models using Adenomatous polyposis coli (Apc) loss-of-functions (LOF) are widely used to mimic β-catenin-dependent tumorigenesis. Considering the low prevalence of APC mutations in human HCCs we aimed to generate hepatic tumors through CTNNB1 exon 3 deletion (βcatΔex3) and to compare them to hepatic tumors with Apc LOF engineered through a frameshift in exon 15 (Apcfs-ex15). Methods We used hepatic-specific and inducible Cre-lox mouse models as well as a hepatic-specific in vivo CRISPR/Cas9 approach using AAV vectors, to generate Apcfs-ex15 and βcatΔex3 hepatic tumors harboring activation of the β-catenin pathway. Tumors generated by the Cre-lox models were analyzed phenotypically using immunohistochemistry and were selected for transcriptomic analysis using RNA-sequencing. Mouse RNAseq data were compared to human RNAseq data (norma...
In MCF-7 (estrogen receptor (ER)+) and in MDA-MB-231 (ER-) cells stably transfected with either e... more In MCF-7 (estrogen receptor (ER)+) and in MDA-MB-231 (ER-) cells stably transfected with either estrogen receptor alpha (ERalpha) or beta (ERbeta) subtype (MDA-MB-231 stably transfected with the mouse ERalpha cDNA (MERA) and MDA-MB-231 stably transfected with the human ERbeta cDNA (HERB), respectively) N-term heat shock protein of 90kDa (hsp90) ligands (geldanamycin and radicicol) and C-term hsp90 ligands (novobiocin) decrease the basal and estradiol (E(2))-induced transcription activity of ER on an estrogen responsive element (ERE)-LUC reporter construct concomitantly with or 1h after E(2) treatment. All hsp90 ligands induced an E(2)- and MG132-inhibited decrease of both ER cell content. However, the kinetics of these degradations are slower than those induced by the selective estrogen receptor down-regulator RU 58668 (RU). This suggests that inhibition of the hsp90 ATPase activity targets both ERs to the 26S proteasome and that hsp90 interacts with both ER subtypes. Rapamycin (Rap...
Journal of Hepatology, 2015
World Journal of Hepatology
Molecular therapy, Apr 1, 2024
Journal of translational medicine, Apr 8, 2024
Methods in molecular biology, 2024
HAL (Le Centre pour la Communication Scientifique Directe), Oct 18, 2013
Les microARN (miARN) sont de petits ARN non-codants contrôlant négativement l'expression de leurs... more Les microARN (miARN) sont de petits ARN non-codants contrôlant négativement l'expression de leurs cibles. Par leur mutiplicité d'action, ils jouent un rôle majeur dans nombre de processi physiologiques et dans la tumorigenèse. L'identification de signatures miARN pour une grande variété de tumeurs, dont les carcinomes hépatocellulaires (CHC), ont mis en évidence le rôle ambivalent des miARN, à la fois oncogène et suppresseur de tumeurs. Dans cette revue, nous faisons un tour d'horizon des connaissances actuelles au sujet de la dérégulation des miARN dans les maladies du foie. Toutes les études dédiées aux miARN sont en faveur de leur utilisation en tant qu'outil diagnostique, pronostique et thérapeutique. Un intérêt tout particulier sera porté aux stratégies thérapeutiques qui ciblent les miARN dans le CHC.
Journal of Steroid Biochemistry and Molecular Biology, 2005
M S-medecine Sciences, Oct 1, 2013
Journal of Hepatology, Apr 1, 2018
to 1 year). Conclusion: This is the first report highlighting the essential role of RuvBL1 for he... more to 1 year). Conclusion: This is the first report highlighting the essential role of RuvBL1 for hepatocyte survival and the impact of its loss on liver carcinogenesis. The increased HCC incidence does not reflect a tumor-suppressor role of RuvBL1, rather, it is the outcome of a chronic regenerative process from staminal precursors. This model may prove useful to investigate the mechanism underlying liver regeneration in the context of chronic hepatic damage.
Le ligand, le promoteur et la lignee cellulaire influencent les capacites transactivatrices des r... more Le ligand, le promoteur et la lignee cellulaire influencent les capacites transactivatrices des recepteurs aux œstrogenes (ER) a et b. Le contexte cellulaire (expression/acetylation de ER/des coregulateurs) module l’activite suppressive de ERb, dependante de son AF1, envers ERa. Trois approches anticancereuses ont ete testees : l’anti-œstrogene pur RU 58668 induit la degradation proteasomale de ERa, reduit sa capacite de transactivation mais affecte peu ERb, facteur de bon pronostic. Les inhibiteurs d’histone-deacetylases, agents pro-apoptotiques et cytostatiques, provoquent la degradation de ERa mais stabilisent ERb. L’association de ces deux agents anticancereux augmente les effets antiproliferatifs et proapoptotiques observes sur des cellules MCF-7 ERa+ERb+ avec ces molecules seules. Enfin, les inhibiteurs de la hsp90, chaperon de ER, provoquent sa degradation proteasomale, inhibent son activite transcriptionnelle, induisent l’apoptose des cellules et bloquent leur proliferation.
Journal of Hepatology, 2022
BACKGROUND AND AIMS One-third of hepatocellular carcinomas (HCCs) harbor mutations activating the... more BACKGROUND AND AIMS One-third of hepatocellular carcinomas (HCCs) harbor mutations activating the β-catenin pathway predominantly via mutations in CTNNB1 gene itself. Mouse models of Apc loss-of-function are widely used to mimic β-catenin-dependent tumorigenesis. Given the low prevalence of APC mutations in human HCCs we aimed to generate liver tumors through CTNNB1 exon 3 deletion (βcatΔex3). We then compared βcatΔex3 liver tumors with liver tumors generated via frameshift in exon 15 of Apc (Apcfs-ex15). METHODS We used hepatocyte-specific and inducible mouse models generated through either a Cre-Lox or a CRISPR/Cas9 approach using AAV vectors. Tumors generated by the Cre-Lox models were phenotypically analyzed using immunohistochemistry and were selected for transcriptomic analysis by RNA-sequencing. Mouse RNAseq data were compared to human RNAseq data (8 normal tissues, 48 HCCs, 9 hepatoblastomas) in an integrative analysis. Tumors generated via CRISPR were analyzed using DNA sequencing and immunohistochemistry. RESULTS Mice with CTNNB1 exon 3 deletion in hepatocytes developed liver tumors indistinguishable from Apcfs-ex15 liver tumors. Both Apcfs-ex15 and βcatΔex3 mouse models induced growth of two phenotypically distinct tumors (differentiated or undifferentiated). Integrative analysis of human and mouse tumors showed that differentiated mouse tumors cluster with well-differentiated human CTNNB1-mutated tumors. Conversely, undifferentiated mouse tumors cluster with human mesenchymal hepatoblastomas and harbor activated YAP signaling. CONCLUSION Apcfs-ex15 and βcatΔex3 mouse models both induce growth of tumors that are transcriptionally similar to either well-differentiated and β-catenin-activated human HCCs or mesenchymal hepatoblastomas. LAY SUMMARY New and easy-to-use transgenic mouse models of liver primary cancers have been generated, with mutations in the gene coding beta-catenin, frequent in both adult and pediatric liver primary cancers. The mice develop both types of cancer, constituting a strong preclinical model.
Gut, 2019
Liver cancer is the second leading cause of cancer-related deaths worldwide, for which therapeuti... more Liver cancer is the second leading cause of cancer-related deaths worldwide, for which therapeutic options are very limited and novel strategies alarmingly needed. The leading risk factor for hepatocellular carcinoma (HCC) is cirrhosis due to HBV and HCV viruses, alcohol abuse, genotoxic exposure and metabolic disorders increasingly associated with diabetes and obesity. HCC is the paradigm of inflammation-associated cancer, with >80% of HCC emerging consecutively to a vast remodelling of liver stroma. To restrain inflammatory response, liver parenchyma physiologically harbours a specific microenvironment to prevent the establishment of inflammation. Immune cells largely orchestrate liver protection, in particular Kupffer cells, the liver macrophages, in partnership with fibroblasts. Nevertheless, when it gets into chronicity, liver inflammation sensitises to cancer development, tumor-associated stroma being recognised as a major hallmark of cancer, as described by Hanahan and Weinberg in 2011.1 During hepatocyte transformation, the surrounding cells, including cancer-associated fibroblasts, hepatic stellate cells, tumour-infiltrating leukocytes and tumour-associated macrophages (TAM) are abnormally activated and/or recruited. These cells secrete a cocktail of growth factors, cytokines and chemokines, which exacerbate liver inflammation and injury in favour of hepatocarcinogenesis.2 Macrophages are the major part of immune cell infiltrates in solid tumours, and the density of macrophages is strongly correlated to poor overall survival, including in HCC. Inversely, myeloid-derived suppressor cells (MDSCs) have emerged as central …
Gut, Jun 19, 2015
Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third o... more Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third of these tumours presents activating mutations of the β-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high, and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by β-catenin, potentially involved in liver tumorigenesis. We used a mouse model, in which β-catenin signalling was overactivated exclusively in the liver by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumours with properties similar to human HCC. We found that miR-34a was regulated by β-catenin, and significantly induced by the overactivation of β-catenin signalling in mouse tumours and in patients with HCC. An inhibitor of miR-34a (locked nucleic acid, LNA-34a) exerted antiproliferative activity in primary cultures of hepatocyte. This inhibition of p...
Copyright © 2011 Angélique Gougelet et al. This is an open access article distributed under the C... more Copyright © 2011 Angélique Gougelet et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Sarcomas are divided into a group with specific alterations and a second presenting a complex karyotype, sometimes difficult to diagnose or with few therapeutic options available. We assessed if miRNA profiling by TaqMan low density arrays could predict the response of undifferentiated rhabdomyosarcoma (RMS) and osteosarcoma to treatment. We showed that miRNA signatures in response to a therapeutic agent (chemotherapy or the mTOR inhibitor RAD-001) were cell and drug specific on cell lines and a rat osteosarcoma model. This miRNA signature was related to cell or tumour sensitivity to this treatment and might be not due to chromosomal aberrations, as revealed by a CGH array analysis of rat tumours. Strikingly, miRNA profiling gave...
Medecine sciences : M/S, 2020
Vers une imagerie métabolique des tumeurs cancéreuses L'imagerie des tumeurs malignes par tomogra... more Vers une imagerie métabolique des tumeurs cancéreuses L'imagerie des tumeurs malignes par tomographie par émission de positons (TEP) utilise une propriété essentielle des cellules cancéreuses : leur métabolisme modifié afin d'acquérir une autonomie énergétique. Suite à l'injection d'un métabolite radio-marqué, la tumeur primaire et ses métastases éventuelles sont visualisées par l'incorporation accrue de ce métabolite dans les cellules tumorales par rapport aux cellules saines adjacentes [1] (➜). L'utilisation de cette technique d'imagerie dans le cancer a fait suite aux travaux
Background and aims One-third of hepatocellular carcinomas (HCCs) have mutations that activate th... more Background and aims One-third of hepatocellular carcinomas (HCCs) have mutations that activate the β-catenin pathway with mostly CTNNB1 mutations. Mouse models using Adenomatous polyposis coli (Apc) loss-of-functions (LOF) are widely used to mimic β-catenin-dependent tumorigenesis. Considering the low prevalence of APC mutations in human HCCs we aimed to generate hepatic tumors through CTNNB1 exon 3 deletion (βcatΔex3) and to compare them to hepatic tumors with Apc LOF engineered through a frameshift in exon 15 (Apcfs-ex15). Methods We used hepatic-specific and inducible Cre-lox mouse models as well as a hepatic-specific in vivo CRISPR/Cas9 approach using AAV vectors, to generate Apcfs-ex15 and βcatΔex3 hepatic tumors harboring activation of the β-catenin pathway. Tumors generated by the Cre-lox models were analyzed phenotypically using immunohistochemistry and were selected for transcriptomic analysis using RNA-sequencing. Mouse RNAseq data were compared to human RNAseq data (norma...
In MCF-7 (estrogen receptor (ER)+) and in MDA-MB-231 (ER-) cells stably transfected with either e... more In MCF-7 (estrogen receptor (ER)+) and in MDA-MB-231 (ER-) cells stably transfected with either estrogen receptor alpha (ERalpha) or beta (ERbeta) subtype (MDA-MB-231 stably transfected with the mouse ERalpha cDNA (MERA) and MDA-MB-231 stably transfected with the human ERbeta cDNA (HERB), respectively) N-term heat shock protein of 90kDa (hsp90) ligands (geldanamycin and radicicol) and C-term hsp90 ligands (novobiocin) decrease the basal and estradiol (E(2))-induced transcription activity of ER on an estrogen responsive element (ERE)-LUC reporter construct concomitantly with or 1h after E(2) treatment. All hsp90 ligands induced an E(2)- and MG132-inhibited decrease of both ER cell content. However, the kinetics of these degradations are slower than those induced by the selective estrogen receptor down-regulator RU 58668 (RU). This suggests that inhibition of the hsp90 ATPase activity targets both ERs to the 26S proteasome and that hsp90 interacts with both ER subtypes. Rapamycin (Rap...
Journal of Hepatology, 2015
World Journal of Hepatology