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53. Sarcoma treatment in the era of molecular medicine

Author

Grünewald, Thomas G. P., Alonso, Marta, Avnet, Sofia, Banito, Ana, Burdach, Stefan, Cidre-Aranaz, Florencia, Di Pompo, Gemma, Distel, Martin, Dorado-Garcia, Heathcliff, Garcia-Castro, Javier, Gonzalez-Gonzalez, Laura, Grigoriadis, Agamemnon E., Kasan, Merve, Koelsche, Christian, Krumbholz, Manuela, Lecanda, Fernando, Lemma, Silvia, Longo, Dario L., Madrigal-Esquivel, Claudia, Morales-Molina, Alvaro, Musa, Julian, Ohmura, Shunya, Ory, Benjamin, Pereira-Silva, Miguel, Perut, Francesca, Rodriguez, Rene, Seeling, Carolin, Al Shaaili, Nada, Shaabani, Shabnam, Shiavone, Kristina, Sinha, Snehadri, Tomazou, Eleni M., Trautmann, Marcel, Vela, Maria, Versleijen-Jonkers, Yvonne M. H., Visgauss, Julia, Zalacain, Marta, Schober, Sebastian J., Lissat, Andrej, English, William R., Baldini, Nicola, Heymann, Dominique, Department of Oral and Maxillofacial Diseases, University of Helsinki, and HUS Helsinki and Uusimaa Hospital District

Subjects
EARLY METABOLIC-RESPONSE, Cancer Research, GASTROINTESTINAL STROMAL TUMORS, 3122 Cancers, bone sarcoma, CONDITIONALLY REPLICATIVE ADENOVIRUS, INFILTRATING T-CELLS, PATIENT-DERIVED XENOGRAFTS, targeted therapy, CIRCULATING TUMOR-CELLS, molecular diagnostics, SOFT-TISSUE SARCOMA, soft tissue sarcoma, CANCER STEM-CELLS, ENDOTHELIAL GROWTH-FACTOR, LIMB-SALVAGE TREATMENT, molecular medicine
Abstract

Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.

Published
2020

58. Exploring Metabolic Adaptations to the Acidic Microenvironment of Osteosarcoma Cells Unveils Sphingosine 1-Phosphate as a Valuable Therapeutic Target

Author

Cortini, Margherita, primary, Armirotti, Andrea, additional, Columbaro, Marta, additional, Longo, Dario Livio, additional, Di Pompo, Gemma, additional, Cannas, Elena, additional, Maresca, Alessandra, additional, Errani, Costantino, additional, Longhi, Alessandra, additional, Righi, Alberto, additional, Carelli, Valerio, additional, Baldini, Nicola, additional, and Avnet, Sofia, additional

Published
2021
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62. Abstract 5909: IDH mutations in G2-3 conventional chondrosarcoma of bone: a mono institutional experience

Author

Setola, Elisabetta, primary, Benini, Stefania, additional, Righi, Alberto, additional, Gamberi, Gabriella, additional, Avnet, Sofia, additional, Carretta, Elisa, additional, Ferrari, Cristina, additional, Palmerini, Emanuela, additional, Lollini, Pier Luigi, additional, Cesari, Marilena, additional, Paioli, Anna, additional, Longhi, Alessandra, additional, Donati, Davide Maria, additional, and Baldini, Nicola, additional

Published
2020
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63. The human tumor microbiome is composed of tumor type–specific intracellular bacteria

Author

Nejman, Deborah, primary, Livyatan, Ilana, additional, Fuks, Garold, additional, Gavert, Nancy, additional, Zwang, Yaara, additional, Geller, Leore T., additional, Rotter-Maskowitz, Aviva, additional, Weiser, Roi, additional, Mallel, Giuseppe, additional, Gigi, Elinor, additional, Meltser, Arnon, additional, Douglas, Gavin M., additional, Kamer, Iris, additional, Gopalakrishnan, Vancheswaran, additional, Dadosh, Tali, additional, Levin-Zaidman, Smadar, additional, Avnet, Sofia, additional, Atlan, Tehila, additional, Cooper, Zachary A., additional, Arora, Reetakshi, additional, Cogdill, Alexandria P., additional, Khan, Md Abdul Wadud, additional, Ologun, Gabriel, additional, Bussi, Yuval, additional, Weinberger, Adina, additional, Lotan-Pompan, Maya, additional, Golani, Ofra, additional, Perry, Gili, additional, Rokah, Merav, additional, Bahar-Shany, Keren, additional, Rozeman, Elisa A., additional, Blank, Christian U., additional, Ronai, Anat, additional, Shaoul, Ron, additional, Amit, Amnon, additional, Dorfman, Tatiana, additional, Kremer, Ran, additional, Cohen, Zvi R., additional, Harnof, Sagi, additional, Siegal, Tali, additional, Yehuda-Shnaidman, Einav, additional, Gal-Yam, Einav Nili, additional, Shapira, Hagit, additional, Baldini, Nicola, additional, Langille, Morgan G. I., additional, Ben-Nun, Alon, additional, Kaufman, Bella, additional, Nissan, Aviram, additional, Golan, Talia, additional, Dadiani, Maya, additional, Levanon, Keren, additional, Bar, Jair, additional, Yust-Katz, Shlomit, additional, Barshack, Iris, additional, Peeper, Daniel S., additional, Raz, Dan J., additional, Segal, Eran, additional, Wargo, Jennifer A., additional, Sandbank, Judith, additional, Shental, Noam, additional, and Straussman, Ravid, additional

Published
2020
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74. 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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85. Immunohistochemical evaluation of bone metastases

Author

Errani, Costantino, primary, Mavrogenis, Andreas F., additional, Megaloikonomos, Panayiotis D., additional, Antoniadou, Thekla, additional, Antonioli, Diego, additional, Avnet, Sofia, additional, Pellacani, Andrea, additional, and Baldini, Nicola, additional

Published
2017
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86. Annual Meeting of the International Society of Cancer Metabolism (ISCaM): Metabolic Networks in Cancer

Author

Baldini, Nicola, primary, De Milito, Angelo, additional, Feron, Olivier, additional, Gillies, Robert J., additional, Michiels, Carine, additional, Otto, Angela M., additional, Pastoreková, Silvia, additional, Pedersen, Stine F., additional, Porporato, Paolo E., additional, Sonveaux, Pierre, additional, Supuran, Claudiu T., additional, and Avnet, Sofia, additional

Published
2017
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87. Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma

Author

Di Pompo, Gemma, primary, Lemma, Silvia, additional, Canti, Lorenzo, additional, Rucci, Nadia, additional, Ponzetti, Marco, additional, Errani, Costantino, additional, Donati, Davide Maria, additional, Russell, Shonagh, additional, Gillies, Robert, additional, Chano, Tokuhiro, additional, Baldini, Nicola, additional, and Avnet, Sofia, additional

Published
2017
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88. Annual meeting of the International Society of Cancer Metabolism (ISCaM): metabolic networks in cancer

Author

UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique, Baldini, Nicola, De Milito, Angelo, Feron, Olivier, Gillies, Robert J, Michiels, Carine, Otto, Angela M, Pastorekova, Silvia, Perdersen, Stine F, Porporato, Paolo, Sonveaux, Pierre, Supuran, Claudiu T, Avnet, Sofia, UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique, Baldini, Nicola, De Milito, Angelo, Feron, Olivier, Gillies, Robert J, Michiels, Carine, Otto, Angela M, Pastorekova, Silvia, Perdersen, Stine F, Porporato, Paolo, Sonveaux, Pierre, Supuran, Claudiu T, and Avnet, Sofia

Abstract

Cancers are metabolic entities wherein cancer cells adapt their metabolism to their oncogenic agenda and microenvironmental influences. Metabolically different cancer cell subpopulations collaborate to optimize nutrient delivery with respect to immediate bioenergetic and biosynthetic needs. They can also metabolically exploit host cells. These metabolic networks are directly linked with cancer progression, treatment, resistance and relapse. Conversely, metabolic alterations in cancer are exploited for anticancer therapy, imaging and personalized medicine. These topics were addressed at the 3rd annual meeting of the International Society of Cancer Metabolism (ISCaM) in Brussels, Belgium, on 26-29 October 2016.

Published
2017

89. MDA-MB-231 breast cancer cells fuel osteoclast metabolism and activity: A new rationale for the pathogenesis of osteolytic bone metastases.

Author

UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, Lemma, Silvia, Di Pompo, Gemma, Porporato, Paolo, Sboarina, Martina, Russell, Shonagh, Gillies, Robert J, Baldini, Nicola, Sonveaux, Pierre, Avnet, Sofia, UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, Lemma, Silvia, Di Pompo, Gemma, Porporato, Paolo, Sboarina, Martina, Russell, Shonagh, Gillies, Robert J, Baldini, Nicola, Sonveaux, Pierre, and Avnet, Sofia

Abstract

Recent progress in dissecting the molecular paracrine circuits of cancer and stromal cells in bone metastases (BM) are offering new options to improve current merely palliative approach. The study of tumor-stroma metabolic interplay may further ameliorate this scenario. In this context, we demonstrated that highly glycolytic MDA-MB-231 cancer cells, that form osteolytic BM in vivo, release a large amount of lactate at a significantly higher level than MCF7 cells. Thus, we speculated that lactate released from carcinoma cells is uptaken and metabolically used by osteoclasts, the key players of osteolysis associated with BM. First, we demonstrated that the release of lactate at the bone site is mediated by monocarboxylate transporter 4 (MCT4), as revealed by immunostaining and MCT4 localization at the plasma membrane of tumor cells in mouse model of BM and in human tissue sections of BM. Then, we showed that in vitro lactate is uptaken by osteoclasts to be used as a fuel for the oxidative metabolism of osteoclasts, ultimately enhancing Type I collagen resorption. The passive transport of lactate into osteoclasts was mediated by MCT1: MCT1 expression is significantly upregulated during osteoclast differentiation and Type I collagen resorption is significantly impaired when osteoclasts are treated with 7-(N-benzyl-N-methylamino)-2-oxo-2H-chromene-3-carboxylic acid, an MCT-1 inhibitor. Together, these data demonstrate that lactate released by glycolytic breast carcinoma cells in the bone microenvironment promotes the formation of osteolytic lesions, and provide the rationale for further studies on the use of MCT1 targeting as a novel therapeutic approach in advanced cancer patients with BM.

Published
2017

90. Annual Meeting of the International Society of Cancer Metabolism (ISCaM):metabolic networks in cancer

Author

Baldini, Nicola, de Milito, Angelo, Feron, Olivier, Gillies, Robert J., Michiels, Carine, Otto, Angela M., Pastoreková, Silvia, Pedersen, Stine Helene Falsig, Porporato, Paolo E., Sonveaux, Pierre, Supuran, Claudiu T., Avnet, Sofia, Baldini, Nicola, de Milito, Angelo, Feron, Olivier, Gillies, Robert J., Michiels, Carine, Otto, Angela M., Pastoreková, Silvia, Pedersen, Stine Helene Falsig, Porporato, Paolo E., Sonveaux, Pierre, Supuran, Claudiu T., and Avnet, Sofia

Published
2017

91. Osteoclast differentiation from human blood precursors on biomimetic calcium-phosphate substrates

Author

Universitat Politècnica de Catalunya. Departament de Ciència dels Materials i Enginyeria Metal·lúrgica, Universitat Politècnica de Catalunya. BBT - Biomaterials, Biomecànica i Enginyeria de Teixits, Istituto Ortopedico Rizzoli, Ciapetti, Gabriela, Pompo, Gemma di, Avnet, Sofia, Martini, Desirée, Díez Escudero, Anna, Montufar Jiménez, Edgar Benjamin, Ginebra Molins, Maria Pau, Baldini, Nicola, Universitat Politècnica de Catalunya. Departament de Ciència dels Materials i Enginyeria Metal·lúrgica, Universitat Politècnica de Catalunya. BBT - Biomaterials, Biomecànica i Enginyeria de Teixits, Istituto Ortopedico Rizzoli, Ciapetti, Gabriela, Pompo, Gemma di, Avnet, Sofia, Martini, Desirée, Díez Escudero, Anna, Montufar Jiménez, Edgar Benjamin, Ginebra Molins, Maria Pau, and Baldini, Nicola

Abstract

The design of synthetic bone grafts to foster bone formation is a challenge in regenerative medicine. Understanding the interaction of bone substitutes with osteoclasts is essential, since osteoclasts not only drive a timely resorption of the biomaterial, but also trigger osteoblast activity. In this study, the adhesion and differentiation of human blood-derived osteoclast precursors (OCP) on two different micro-nanostructured biomimetic hydroxyapatite materials consisting in coarse (HA-C) and fine HA (HA-F) crystals, in comparison with sintered stoichiometric HA (sin-HA, reference material), were investigated. Osteoclasts were induced to differentiate by RANKL-containing supernatant using cell/substrate direct and indirect contact systems, and calcium (Ca++) and phosphorus (P5+) in culture medium were measured. We observed that OCP adhered to the experimental surfaces, and that osteoclast-like cells formed at a rate influenced by the micro- and nano-structure of HA, which also modulate extracellular Ca++. Qualitative differences were found between OCP on biomimetic HA-C and HA-F and their counterparts on plastic and sin-HA. On HA-C and HA-F cells shared typical features of mature osteoclasts, i.e. podosomes, multinuclearity, tartrate acid phosphatase (TRAP)-positive staining, and TRAP5b-enzyme release. However, cells were less in number compared to those on plastic or on sin-HA, and they did not express some specific osteoclast markers. In conclusion, blood-derived OCP are able to attach to biomimetic and sintered HA substrates, but their subsequent fusion and resorptive activity are hampered by surface micro-nano-structure. Indirect cultures suggest that fusion of OCP is sensitive to topography and to extracellular calcium., Preprint

Published
2017

92. Energy metabolism in osteoclast formation and activity.

Author

UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique, Lemma, Silvia, Sboarina, Martina, Porporato, Paolo, Zini, Nicoletta, Sonveaux, Pierre, Di Pompo, Gemma, Baldini, Nicola, Avnet, Sofia, UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique, Lemma, Silvia, Sboarina, Martina, Porporato, Paolo, Zini, Nicoletta, Sonveaux, Pierre, Di Pompo, Gemma, Baldini, Nicola, and Avnet, Sofia

Abstract

Osteoclastogenesis and osteolysis are energy-consuming processes supported by high metabolic activities. In human osteoclasts derived from the fusion of monocytic precursors, we found a substantial increase in the number of mitochondria with differentiation. In mature osteoclasts, mitochondria were also increased in size, rich of cristae and arranged in a complex tubular network. When compared with immature cells, fully differentiated osteoclasts showed higher levels of enzymes of the electron transport chain, a higher mitochondrial oxygen consumption rate and a lower glycolytic efficiency, as evaluated by extracellular flux analysis and by the quantification of metabolites in the culture supernatant. Thus, oxidative phosphorylation appeared the main bioenergetic source for osteoclast formation. Conversely, we found that bone resorption mainly relied on glycolysis. In fact, osteoclast fuelling with galactose, forcing cells to depend on Oxidative Phosphorylation by reducing the rate of glycolysis, significantly impaired Type I collagen degradation, whereas non-cytotoxic doses of rotenone, an inhibitor of the mitochondrial complex I, enhanced osteoclast activity. Furthermore, we found that the enzymes associated to the glycolytic pathway are localised close to the actin ring of polarised osteoclasts, where energy-demanding activities associated with bone degradation take place. In conclusion, we demonstrate that the energy required for osteoclast differentiation mainly derives from mitochondrial oxidative metabolism, whereas the peripheral cellular activities associated with bone matrix degradation are supported by glycolysis. A better understanding of human osteoclast energy metabolism holds the potential for future therapeutic interventions aimed to target osteoclast activity in different pathological conditions of bone.

Published
2016

93. Metabolism and microenvironment in cancer plasticity

Author

Baldini, Nicola, Sonveaux, Pierre, De Milito, Angelo, Supuran, Claudiu T., Otto, Angela M., Stock, Christian M., Pedersen, Stine Helene Falsig, Favicchio, Rosy, Avnet, Sofia, Baldini, Nicola, Sonveaux, Pierre, De Milito, Angelo, Supuran, Claudiu T., Otto, Angela M., Stock, Christian M., Pedersen, Stine Helene Falsig, Favicchio, Rosy, and Avnet, Sofia

Published
2016

95. Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance

Author

Avnet, Sofia, primary, Lemma, Silvia, additional, Cortini, Margherita, additional, Pellegrini, Paola, additional, Perut, Francesca, additional, Zini, Nicoletta, additional, Kusuzaki, Katsuyuki, additional, Chano, Tokuhiro, additional, Grisendi, Giulia, additional, Dominici, Massimo, additional, De Milito, Angelo, additional, and Baldini, Nicola, additional

Published
2016
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100. RAB39A: a Rab small GTPase with a prominent role in cancer stemness.

Author

Tokuhiro Chano and Avnet, Sofia

Subjects
*GUANOSINE triphosphatase, *CANCER cells, *INTRACELLULAR membranes, *IMMUNITY, *CELL proliferation
Abstract

RAB39A is a Rab small GTPase that localizes at distinct subcellular compartments and regulates intracellular membrane trafficking pathways in vertebrate cells. RAB39A interacts with various molecules and modulates vesicular trafficking that regulates multiple biological pathways such as neuronal differentiation and/or autophagy. Among these pathways are Hippo and Notch signallings, microtubular organization and mitophagy/autophagy. Although RAB39A has never been studied in cancer biology, it has been recently shown to promote cancer stemness and tumorigenesis. Molecular pathways regulated by RAB39A are transcriptionally maintained by the formation of molecular complex with RXRB, NCOR and HDAC that also contribute to cancer stemness. In this review, we provide current knowledge on the oncogenic function of RAB39A and summarize the effect of different microenvironments on RAB39A activity and subcellular localization in cancer cells. [ABSTRACT FROM AUTHOR]

Published
2018
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