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1. PAX3-FOXO1 uses its activation domain to recruit CBP/P300 and shape RNA Pol2 cluster distribution

Author

Asante, Yaw, Benischke, Katharina, Osman, Issra, Ngo, Quy A., Wurth, Jakob, Laubscher, Dominik, Kim, Hyunmin, Udhayakumar, Bhavatharini, Khan, Md Imdadul H., Chin, Diana H., Porch, Jadon, Chakraborty, Maharshi, Sallari, Richard, Delattre, Olivier, Zaidi, Sakina, Morice, Sarah, Surdez, Didier, Danielli, Sara G., Schäfer, Beat W., Gryder, Berkley E., and Wachtel, Marco

Published
2023
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7. PAX3-FOXO1 uses its activation domain to recruit CBP/P300 and shape RNA Pol2 cluster distribution

Author

Asante, Yaw; https://orcid.org/0000-0002-6924-8632, Benischke, Katharina, Osman, Issra; https://orcid.org/0000-0001-5918-4543, Ngo, Quy A, Wurth, Jakob; https://orcid.org/0000-0002-1328-7122, Laubscher, Dominik, Kim, Hyunmin; https://orcid.org/0000-0003-0835-5044, Udhayakumar, Bhavatharini, Khan, Md Imdadul H; https://orcid.org/0000-0001-8002-5600, Chin, Diana H; https://orcid.org/0000-0002-1645-3552, Porch, Jadon, Chakraborty, Maharshi, Sallari, Richard, Delattre, Olivier; https://orcid.org/0000-0002-8730-2276, Zaidi, Sakina; https://orcid.org/0000-0001-9128-0287, Morice, Sarah, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, Danielli, Sara G; https://orcid.org/0000-0003-3101-3114, Schäfer, Beat W; https://orcid.org/0000-0001-5988-2915, Gryder, Berkley E; https://orcid.org/0000-0003-0130-2302, Wachtel, Marco; https://orcid.org/0000-0002-6077-3692, Asante, Yaw; https://orcid.org/0000-0002-6924-8632, Benischke, Katharina, Osman, Issra; https://orcid.org/0000-0001-5918-4543, Ngo, Quy A, Wurth, Jakob; https://orcid.org/0000-0002-1328-7122, Laubscher, Dominik, Kim, Hyunmin; https://orcid.org/0000-0003-0835-5044, Udhayakumar, Bhavatharini, Khan, Md Imdadul H; https://orcid.org/0000-0001-8002-5600, Chin, Diana H; https://orcid.org/0000-0002-1645-3552, Porch, Jadon, Chakraborty, Maharshi, Sallari, Richard, Delattre, Olivier; https://orcid.org/0000-0002-8730-2276, Zaidi, Sakina; https://orcid.org/0000-0001-9128-0287, Morice, Sarah, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, Danielli, Sara G; https://orcid.org/0000-0003-3101-3114, Schäfer, Beat W; https://orcid.org/0000-0001-5988-2915, Gryder, Berkley E; https://orcid.org/0000-0003-0130-2302, and Wachtel, Marco; https://orcid.org/0000-0002-6077-3692

Abstract

Activation of oncogenic gene expression from long-range enhancers is initiated by the assembly of DNA-binding transcription factors (TF), leading to recruitment of co-activators such as CBP/p300 to modify the local genomic context and facilitate RNA-Polymerase 2 (Pol2) binding. Yet, most TF-to-coactivator recruitment relationships remain unmapped. Here, studying the oncogenic fusion TF PAX3-FOXO1 (P3F) from alveolar rhabdomyosarcoma (aRMS), we show that a single cysteine in the activation domain (AD) of P3F is important for a small alpha helical coil that recruits CBP/p300 to chromatin. P3F driven transcription requires both this single cysteine and CBP/p300. Mutants of the cysteine reduce aRMS cell proliferation and induce cellular differentiation. Furthermore, we discover a profound dependence on CBP/p300 for clustering of Pol2 loops that connect P3F to its target genes. In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in aRMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription.

Published
2023

10. Involvement of the TGF-β Signaling Pathway in the Development of YAP-Driven Osteosarcoma Lung Metastasis

Author

Morice, Sarah, Danieau, Geoffroy, Tesfaye, Robel, Mullard, Mathilde, Brion, Régis, Dupuy, Maryne, Ory, Benjamin, Brounais-Le Royer, Bénédicte, Corre, Isabelle, Redini, Françoise, Verrecchia, Franck, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), and CORRE, Isabelle

Subjects
[SDV] Life Sciences [q-bio], Oncology, Hippo, TGF-b/Smad3, TEAD, osteosarcoma, [SDV]Life Sciences [q-bio], lung metastases, YAP, Original Research, TGF-β/Smad3
Abstract

Background The poor survival rate of patients with osteosarcoma (OS), specifically with metastases at diagnosis, undergoes the urgency to develop new therapeutic strategies. Although we recently demonstrated the key role of YAP/TEAD signaling in the growth of OS primary tumor, the molecular mechanisms by which YAP regulates metastases development remain poorly understood. Methods The molecular mechanisms by which YAP regulates metastases development were studied using an overexpression of mutated forms of YAP able or not able to interact with TEAD. Molecular signatures were identified using RNA-sequencing analysis and gene set enrichment. Interactions between YAP and Smad3 were studied using proximity ligation assay (PLA), immunoprecipitation, and promoter/specific gene assays. The involvement of the TGF-β pathway in the ability of YAP to stimulate metastatic development in vivo was studied using an inhibitor of the TGF-β cascade in a preclinical model of OS and in vitro on the ability of OS cells to migrate and invade. Results Our work shows that a high YAP expression is associated with the presence of lung metastases which predicts a poor prognosis. Molecular analysis indicates that TGF-β signaling is involved in YAP-driven osteosarcoma cell pro-migratory phenotype, epithelial mesenchymal transition, cell migration, and in vivo lung metastasis development. Regardless of its ability to bind to TEAD, YAP interacts with Smad3 and stimulates the transcriptional activity of TGF-β/Smad3, thereby enhancing the ability of TGF-β to stimulate lung metastasis development. Conclusions We demonstrated the crucial involvement of the TGF-β/Smad3 signaling pathway in YAP-driven lung metastasis development in OS.

Published
2021
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11. Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619

Author

Lavaud, Mélanie, primary, Mullard, Mathilde, additional, Tesfaye, Robel, additional, Amiaud, Jérôme, additional, Legrand, Mélanie, additional, Danieau, Geoffroy, additional, Brion, Régis, additional, Morice, Sarah, additional, Regnier, Laura, additional, Dupuy, Maryne, additional, Brounais-Le Royer, Bénédicte, additional, Lamoureux, François, additional, Ory, Benjamin, additional, Rédini, Françoise, additional, and Verrecchia, Franck, additional

Published
2021
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12. ICG-001, an Inhibitor of the β-Catenin and cAMP Response Element-Binding Protein Dependent Gene Transcription, Decreases Proliferation but Enhances Migration of Osteosarcoma Cells

Author

Danieau, Geoffroy, primary, Morice, Sarah, additional, Renault, Sarah, additional, Brion, Régis, additional, Biteau, Kevin, additional, Amiaud, Jérôme, additional, Cadé, Marie, additional, Heymann, Dominique, additional, Lézot, Frédéric, additional, Verrecchia, Franck, additional, Rédini, Françoise, additional, and Brounais-Le Royer, Bénédicte, additional

Published
2021
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13. Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors

Author

Talbot, Julie, Dupuy, Maryne, Morice, Sarah, Redini, Françoise, Verrecchia, Franck, Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), and maurice, sandrine

Subjects
Male, Epithelial-Mesenchymal Transition, lcsh:QR1-502, Gene Expression, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Communication, Review, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Models, Biological, lcsh:Microbiology, connexin 43, gap junction, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Animals, Humans, metastatic process, Neoplasm Metastasis, primary tumor growth, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cell Proliferation, Mice, Knockout, bone tumors, metastatic process 29 30, Gap Junctions, Prostatic Neoplasms, Female, Bone Remodeling
Abstract

International audience; Despite research and clinical advances during the past decades, bone cancers remain 11 a leading cause of death worldwide. There is a low survival rate for patients with primary bone 12 tumors such as osteosarcoma and Ewing's sarcoma or secondary bone tumors such as bone 13 metastases from prostate carcinoma. Gap junctions are specialized plasma membrane 14 structures consisting of transmembrane channels that directly link the cytoplasm of adjacent 15 cells, thereby enabling the direct exchange of small signaling molecules between cells. 16 Discoveries of human genetic disorders due to genetic mutations in gap junction proteins 17 (connexins) and experimental data using connexin knockout mice have provided significant 18 evidence that gap junctional intercellular communication (Gj) is crucial for tissue function. 19 Thus, the dysfunction of Gj may be responsible for the development of some diseases. Gj is 20 thus a main mechanism for tumor cells to communicate with other tumor cells and their 21 surrounding microenvironment to survive and proliferate. If it is well accepted that a low level 22 of connexin expression favors cancer cell proliferation and therefore primary tumor 23 development, more evidence is suggesting that a high level of connexin expression stimulates 24 various cellular process such as intravasation, extravasation or migration of metastatic cells. If 25 so, connexin expression would facilitate secondary tumor dissemination. This paper discusses 26 evidence that suggests that connexin 43 plays an antagonistic role in the development of 27 primary bone tumors as a tumor suppressor and secondary bone tumors as a tumor promoter.

Published
2020
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14. Hippo/YAP Signaling Pathway: A Promising Therapeutic Target in Bone Paediatric Cancers?

Author

Morice, Sarah, Danieau, Geoffroy, Rédini, Françoise, Brounais-Le-Royer, Bénédicte, Verrecchia, Franck, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), maurice, sandrine, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
[SDV]Life Sciences [q-bio], skeletal development, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, hippo signaling pathway, [SDV] Life Sciences [q-bio], Sonic Hedgehog, [SDV.CAN] Life Sciences [q-bio]/Cancer, osteosarcoma, YAP, Ewing sarcoma, Gli
Abstract

International audience; Osteosarcoma and Ewing sarcoma are the most prevalent bone pediatric tumors. Despite intensive basic and medical research studies to discover new therapeutics and to improve current treatments, almost 40% of osteosarcoma and Ewing sarcoma patients succumb to the disease. Patients with poor prognosis are related to either the presence of metastases at diagnosis or resistance to chemotherapy. Over the past ten years, considerable interest for the Hippo/YAP signaling pathway has taken place within the cancer research community. This signaling pathway operates at different steps of tumor progression: Primary tumor growth, angiogenesis, epithelial to mesenchymal transition, and metastatic dissemination. This review discusses the current knowledge about the involvement of the Hippo signaling pathway in cancer and specifically in paediatric bone sarcoma progression.

Published
2020
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17. Sonic Hedgehog Signature in Pediatric Primary Bone Tumors: Effects of the GLI Antagonist GANT61 on Ewing’s Sarcoma Tumor Growth

Author

Mullard, Mathilde, primary, Cadé, Marie, additional, Morice, Sarah, additional, Dupuy, Maryne, additional, Danieau, Geoffroy, additional, Amiaud, Jérome, additional, Renault, Sarah, additional, Lézot, Frédéric, additional, Brion, Régis, additional, Thepault, Rose Anne, additional, Ory, Benjamin, additional, Lamoureux, François, additional, Corre, Isabelle, additional, Brounais-LeRoyer, Bénédicte, additional, Rédini, Françoise, additional, and Verrecchia, Franck, additional

Published
2020
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19. Abstract A29: Respective role of TEAD and Smad signaling in YAP-mediated osteosarcoma tumor growth and lung metastatic development

Author

Morice, Sarah, primary, Danieau, Geoffroy, additional, Mullard, Mathilde, additional, Amiaud, Jérôme, additional, Brion, Régis, additional, Renault, Sarah, additional, Tesfaye, Robel, additional, Dupuy, Maryne, additional, Talbot, Julie, additional, Ory, Benjamin, additional, Brounais-Le Royer, Bénédicte, additional, Corre, Isabelle, additional, Brouchet-Gomez, Anne, additional, Rédini, Françoise, additional, and Verrecchia, Franck, additional

Published
2020
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22. New Insights about the Wnt/β-Catenin Signaling Pathway in Primary Bone Tumors and Their Microenvironment: A Promising Target to Develop Therapeutic Strategies?

Author

Danieau, Geoffroy, Morice, Sarah, Rédini, Françoise, Verrecchia, Franck, Brounais-Le Royer, Benedicte, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), maurice, sandrine, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
bone tumor microenvironment, Adolescent, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], bone sarcoma, Antineoplastic Agents, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Review, Bone and Bones, lcsh:Chemistry, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Tumor Microenvironment, Humans, Molecular Targeted Therapy, Child, lcsh:QH301-705.5, Wnt Signaling Pathway, beta Catenin, Osteosarcoma, Wnt/β-catenin, Neovascularization, Pathologic, Proto-Oncogene Proteins c-ets, Survival Analysis, Gene Expression Regulation, Neoplastic, [SDV] Life Sciences [q-bio], lcsh:Biology (General), lcsh:QD1-999, Lymphatic Metastasis, RNA-Binding Protein EWS
Abstract

International audience; Osteosarcoma and Ewing sarcoma are the most common malignant primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation specifically for Ewing sarcoma, associated with tumor resection. However, patient survival has not evolved for the past decade and remains closely related to the response of tumor cells to chemotherapy, reaching around 75% at 5 years for patients with localized forms of osteosarcoma or Ewing sarcoma but less than 30% in metastatic diseases and patients resistant to initial chemotherapy. Despite Ewing sarcoma being characterized by specific EWSR1-ETS gene fusions resulting in oncogenic transcription factors, currently, no targeted therapy could be implemented. It seems even more difficult to develop a targeted therapeutic strategy in osteosarcoma which is characterized by high complexity and heterogeneity in genomic alterations. Nevertheless, the common point between these different bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Therefore, targeting different actors of the bone tumor microenvironment has been hypothesized to develop new therapeutic strategies. In this context, it is well known that the Wnt/β-catenin signaling pathway plays a key role in cancer development, including osteosarcoma and Ewing sarcoma as well as in bone remodeling. Moreover, recent studies highlight the implication of the Wnt/β-catenin pathway in angiogenesis and immuno-surveillance, two key mechanisms involved in metastatic dissemination. This review focuses on the role played by this signaling pathway in the development of primary bone tumors and the modulation of their specific microenvironment. Keywords: Wnt/β-catenin; bone sarcoma; bone tumor microenvironment 1. Primary Bone Tumors: Osteosarcoma and Ewing Sarcoma Osteosarcoma and Ewing sarcoma are the most common primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation for Ewing sarcoma, associated with tumor resection. However, the 5-year survival rates have not been improved during the last decades reaching 70-80% for patients with localized forms, but less than 30% in metastatic diseases and patients resistant to initial chemotherapy [1-5]. Osteosarcoma that mainly occurs at the ends of long bones is not associated with any clinical signs except severe pain or spontaneous fracture. Osteosarcoma does not express specific oncogenic markers but exhibits a large number and variety of genetic alterations. Ewing sarcoma is a tumor composed of small undifferentiated round cells that can appear mainly in bones but also in soft tissues in 15% of Int.

Published
2019
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23. Contributors

Author

Albiach, Carlos Ferrer, Alix-Panabières, C., Amary, Fernanda, Angelini, Andrea, Arias-Pinilla, Gustavo A., Arredondo Carrera, Hector M., Avnet, Sofia, Bagguley, Dominic, Baldini, Nicola, Blay, Jean-Yves, Blin-Wakkach, Claudine, Bonnelye, Edith, Bouvier, Corinne, Bovée, J.V.M.G., Brahmi, Mehdi, Brown, Janet, Brown, Thomas J., Brown, Janet E., Bruland, Ø.S., Camañes, Teresa Piquer, Campbell, Preston, Carrasco, Giovana, Chappard, Daniel, Chau, Michael M., Chow, Edward, Christoulas, Dimitrios, Cleton-Jansen, Anne-Marie, Clézardin, Philippe, Clohisy, Denis R., Cochonneau, Denis, Coleman, Robert, Corradini, Nadege, Daescu, Ovidiu, Daldrup-Link, Heike, Dean, Dylan C., de Pinieux, Gonzague, Duan, Zhenfeng, Dufresne, Armelle, Dupuy, Maryne, Dutour, A., Edwards, Claire M., Emmanuel, Jouglar, Fei, Fei, Flanagan, Adrienne M., Florent Elefteriou, Forsyth, Ramses, Fournier, Pierrick G.J., Gambera, Stefano, Gao, Dingcheng, García-Castro, Javier, George, Christopher, Georges, Steven, Gomez-Brouchet, Anne, Gouin, Francois, Grigoriadis, Agamemnon E., Groenewoud, Arwin, Grünewald, Thomas G.P., Halper, Julia, Han, Yujiao, Harada, Shuko, Hardes, Jendrik, Hatina, Jiri, Heymann, Marie-Francoise, Heymann, Dominique, Hicks, David G., Hiemcke-Jiwa, L.S., Ho, Tina Thi, Hogendoorn, Pancras C.W., Holen, Ingunn, Horas, Konstantin, Hornicek, Francis J., Idris, Aymen I., Iduarte, Brenda I., Ilaslan, Hakan, James, Victoria, Jayaram, Prem Ruben, Jouglar, Emmanuel, Joyce Wang, Yan-Ran, Juárez, Patricia, Juzeniene, A., Kang, Yibin, Kint, Mathijs, Knowles, Helen J., Kontny, Udo, Lamoureux, Francois, Larsen, R.H., Lavaud, Mélanie, Lawrentschuk, Nathan, Lawson, Michelle A., Le-Royer, Bénédicte Brounais, Leavey, Patrick, Lecanda, Fernando, Lee, Jiyun, Legrand, Mélanie, Lézot, Frédéric, Li, Shibo, Lim, Fiona, Lin, Chun-Yu, Lissat, Andrej, Lopez-Guajardo, Ana, Luc, Ollivier, Ludwig, Joseph, Määttä, Jorma A., Macías, Virginia Morillo, Madel, Maria-Bernadette, Mallinson, Paul I., Marec-Berard, Perrine, Marques, Carina, Masson, Ingrid, Maurizi, Antonio, Mavrogenis, Andreas F., Melo, Camila M., Menéndez, Sofía T., Michael, Nichole, Mikkilineni, Himabindu, Mittal, Vivek, Morice, Sarah, Munk, Peter L., Muñoz-Garcia, Javier, Munoz, Marcia A., Ntanasis-Stathopoulos, Ioannis, Omran, Oumaima, Ong, Sean, Ory, Benjamin, Ottewell, Penelope D., Ouellette, Hugue A., Pang, Hui, Pantel, K., Paterson, Alexander H.G., Patiño-García, Ana, Peneder, Peter, Perennec, Tanguy, Puppo, Margherita, Rajarubendra, Neiroshan, Raman, Srinivas, Revheim, M.E., Richert, I., Richter, Günther, Rodríguez, René, Rogers, Michael J., Rucci, Nadia, Ruggieri, Pietro, Saleh, Lubaid, Seibel, Markus J., Siegal, Gene P., Snaar-Jagalska, B. Ewa, Sousa, Sofia, Squire, Jeremy A., Streitbuerger, Arne, Sundaram, Murali, Supiot, Stéphane, Talbot, Julie, Tallegas, Matthias, Téllez-Gabriel, Marta, Terpos, Evangelos, Thanindratarn, Pichaya, Thompson, Erik W., Tirabosco, Roberto, Tirode, Franck, Tomazou, Eleni M., Tötzl, Marcus, Turner, Bradley M., Valentine, Martin, Valluru, Manoj K., Vaz, Gualter, Verrecchia, Franck, Wang, Ning, Wei, Shi, Wesson, Fern, Wood, Steven L., Xu, Liangcheng Henry, Yan, Yet Yen, You, Lidan, and -F. Zhang, Xiang H.

Published
2022
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25. Connexin43 intercellular communication drives the early differentiation of human bone marrow stromal cells into osteoblasts.

Author

Talbot, Julie, Brion, Régis, Lamora, Audrey, Mullard, Mathilde, Morice, Sarah, Heymann, Dominique, and Verrecchia, Franck

Subjects
BONE marrow physiology, STROMAL cells, OSTEOBLASTS, CELL communication, CONNEXIN 43, GAP junctions (Cell biology)
Abstract

Although it has been demonstrated that human bone marrow stromal cells (hBMSCs) express the ubiquitous connexin43 (Cx43) and form functional gap junctions, their role in the early differentiation of hBMSCs into osteoblasts remains poorly documented. Using in vitro assays, we show that Cx43 expression and gap junctional intercellular communication (GJIC) are increased during the differentiation of hBMSCs into osteoblasts, both at the protein and mRNA levels. Two independent procedures to reduce GJIC, a pharmacological approach with GJIC inhibitors (18α-glycyrrhetinic acid and Gap27 peptide) and a molecular approach using small interfering RNA against Cx43, demonstrated that the presence of Cx43 and functional junctional channels are essential to the ability of hBMSCs to differentiate into osteoblasts in vitro. In addition, a reduced GJIC decreases the expression of Runx2, the major transcription factor implicated in the control of osteoblast commitment and early differentiation of hBMSCs into osteoblasts, suggesting that GJIC mediated by Cx43 is implicated in this process. Together our results demonstrate that GJIC mediated by the Cx43 channels plays a central role throughout the differentiation of hBMSC into osteoblasts, from the early stages to the process of mineralization. [ABSTRACT FROM AUTHOR]

Published
2018
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26. Evaluation of the Role of AXL in Fusion-positive Pediatric Rhabdomyosarcoma Identifies the Small-molecule Inhibitor Bemcentinib (BGB324) as Potent Chemosensitizer.

Author

Danielli SG, Wurth J, Morice S, Kisele S, Surdez D, Delattre O, Bode PK, Wachtel M, and Schäfer BW

Subjects
Animals, Child, Humans, Mice, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Protein Kinase Inhibitors pharmacology, Xenograft Model Antitumor Assays, Axl Receptor Tyrosine Kinase, Benzocycloheptenes pharmacology, Rhabdomyosarcoma drug therapy, Rhabdomyosarcoma pathology, Rhabdomyosarcoma genetics
Abstract

Rhabdomyosarcoma (RMS) is a highly aggressive pediatric cancer with features of skeletal muscle differentiation. More than 80% of the high-risk patients ultimately fail to respond to chemotherapy treatment, leading to limited therapeutic options and dismal prognostic rates. The lack of response and subsequent tumor recurrence is driven in part by stem cell-like cells, the tumor subpopulation that is enriched after treatment, and characterized by expression of the AXL receptor tyrosine kinase (AXL). AXL mediates survival, migration, and therapy resistance in several cancer types; however, its function in RMS remains unclear. In this study, we investigated the role of AXL in RMS tumorigenesis, migration, and chemotherapy response, and whether targeting of AXL with small-molecule inhibitors could potentiate the efficacy of chemotherapy. We show that AXL is expressed in a heterogeneous manner in patient-derived xenografts (PDX), primary cultures and cell line models of RMS, consistent with its stem cell-state selectivity. By generating a CRISPR/Cas9 AXL knock-out and overexpressing models, we show that AXL contributes to the migratory phenotype of RMS, but not to chemotherapy resistance. Instead, pharmacologic blockade with the AXL inhibitors bemcentinib (BGB324), cabozantinib and NPS-1034 rapidly killed RMS cells in an AXL-independent manner and augmented the efficacy of the chemotherapeutics vincristine and cyclophosphamide. In vivo administration of the combination of bemcentinib and vincristine exerted strong antitumoral activity in a rapidly progressing PDX mouse model, significantly reducing tumor burden compared with single-agent treatment. Collectively, our data identify bemcentinib as a promising drug to improve chemotherapy efficacy in patients with RMS., (©2024 The Authors; Published by the American Association for Cancer Research.)

Published
2024
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27. Involvement of the TGF-β Signaling Pathway in the Development of YAP-Driven Osteosarcoma Lung Metastasis.

Author

Morice S, Danieau G, Tesfaye R, Mullard M, Brion R, Dupuy M, Ory B, Brounais-Le Royer B, Corre I, Redini F, and Verrecchia F

Abstract

Background: The poor survival rate of patients with osteosarcoma (OS), specifically with metastases at diagnosis, undergoes the urgency to develop new therapeutic strategies. Although we recently demonstrated the key role of YAP/TEAD signaling in the growth of OS primary tumor, the molecular mechanisms by which YAP regulates metastases development remain poorly understood., Methods: The molecular mechanisms by which YAP regulates metastases development were studied using an overexpression of mutated forms of YAP able or not able to interact with TEAD. Molecular signatures were identified using RNA-sequencing analysis and gene set enrichment. Interactions between YAP and Smad3 were studied using proximity ligation assay (PLA), immunoprecipitation, and promoter/specific gene assays. The involvement of the TGF-β pathway in the ability of YAP to stimulate metastatic development in vivo was studied using an inhibitor of the TGF-β cascade in a preclinical model of OS and in vitro on the ability of OS cells to migrate and invade., Results: Our work shows that a high YAP expression is associated with the presence of lung metastases which predicts a poor prognosis. Molecular analysis indicates that TGF-β signaling is involved in YAP-driven osteosarcoma cell pro-migratory phenotype, epithelial mesenchymal transition, cell migration, and in vivo lung metastasis development. Regardless of its ability to bind to TEAD, YAP interacts with Smad3 and stimulates the transcriptional activity of TGF-β/Smad3, thereby enhancing the ability of TGF-β to stimulate lung metastasis development., Conclusions: We demonstrated the crucial involvement of the TGF-β/Smad3 signaling pathway in YAP-driven lung metastasis development in OS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Morice, Danieau, Tesfaye, Mullard, Brion, Dupuy, Ory, Brounais-Le Royer, Corre, Redini and Verrecchia.)

Published
2021
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