Sandy ADJEMIAN PORTELA CATANI

Pós-doutorado

Idiomas

Áreas de atuação

Orientou

Produções bibliográficas

• MA, YUTING ; ADJEMIAN, SANDY ; GALLUZZI, LORENZO ; ZITVOGEL, LAURENCE ; KROEMER, GUIDO . Chemokines and chemokine receptors required for optimal responses to anticancer chemotherapy. OncoImmunology , v. 3, p. e27663, 2014.

• 2013 NISO-SANTANO, MIREIA ; SHEN, SHENSI ; ADJEMIAN, SANDY ; MALIK, SHOAIB AHMAD ; MARIÑO, GUILLERMO ; LACHKAR, SYLVIE ; SENOVILLA, LAURA ; KEPP, OLIVER ; GALLUZZI, LORENZO ; MAIURI, MARIA CHIARA ; KROEMER, GUIDO . Direct interaction between STAT3 and EIF2AK2 controls fatty acid-induced autophagy. Autophagy (Georgetown, TX) , v. 9, p. 19-21, 2013.

• 2013 MA, YUTING ADJEMIAN, SANDY MATTAROLLO, STEPHEN R. YAMAZAKI, TAKAHIRO AYMERIC, LAETITIA YANG, HENG PORTELA CATANI, JOÃO PAULO HANNANI, DALIL DURET, HELENE STEEGH, KIM MARTINS, ISABELLE SCHLEMMER, FREDERIC MICHAUD, MICKAËL KEPP, OLIVER SUKKURWALA, ABDUL QADER MENGER, LAURIE VACCHELLI, ERIKA DROIN, NATHALIE GALLUZZI, LORENZO KRZYSIEK, ROMAN GORDON, SIAMON TAYLOR, PHILIP R. VAN ENDERT, PETER SOLARY, ERIC SMYTH, MARK J. , et al. ZITVOGEL, LAURENCE KROEMER, GUIDO ; Anticancer Chemotherapy-Induced Intratumoral Recruitment and Differentiation of Antigen-Presenting Cells. Immunity (Cambridge, Mass.) , v. 38, p. 729-741, 2013.

• 2013 SPAGGIARI, SABRINA ; KEPP, OLIVER ; RELLO-VARONA, SANTIAGO ; CHABA, KARIMAN ; ADJEMIAN, SANDY ; PYPE, JAN ; GALLUZZI, LORENZO ; LEMAIRE, MARC ; KROEMER, GUIDO . Antiapoptotic activity of argon and xenon. Cell Cycle (Georgetown, Tex.) , v. 12, p. 2636-2642, 2013.

• 2013 YAMAZAKI, T ; HANNANI, D ; POIRIER-COLAME, V ; LADOIRE, S ; LOCHER, C ; SISTIGU, A ; PRADA, N ; ADJEMIAN, S ; CATANI, J PP ; FREUDENBERG, M ; GALANOS, C ; ANDRÉ, F ; KROEMER, G ; ZITVOGEL, L . Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists. Cell Death and Differentiation , v. 21, p. 69-78, 2013.

• 2013 MA, Y. ; MATTAROLLO, S. R. ; ADJEMIAN, S. ; YANG, H. ; AYMERIC, L. ; HANNANI, D. ; PORTELA CATANI, J. P. ; DURET, H. ; TENG, M. W. L. ; KEPP, O. ; WANG, Y. ; SISTIGU, A. ; SCHULTZE, J. L. ; STOLL, G. ; GALLUZZI, L. ; ZITVOGEL, L. ; SMYTH, M. J. ; KROEMER, G. . CCL2/CCR2-dependent recruitment of functional antigen-presenting cells into tumors upon chemotherapy. Cancer Research (Chicago, Ill.) , v. 74, p. 436, 2013.

• 2013 KEPP, OLIVER ; MENGER, LAURIE ; VACCHELLI, ERIKA ; LOCHER, CLARA ; ADJEMIAN, SANDY ; YAMAZAKI, TAKAHIRO ; MARTINS, ISABELLE ; SUKKURWALA, ABDUL QADER ; MICHAUD, MICHAEL ; SENOVILLA, LAURA ; GALLUZZI, LORENZO ; KROEMER, GUIDO ; ZITVOGEL, LAURENCE . Crosstalk between ER stress and immunogenic cell death. Cytokine & Growth Factor Reviews , v. 24, p. 311-318, 2013.

• MA, YUTING ; ADJEMIAN, SANDY ; YANG, HENG ; CATANI, JOÃO PAULO PORTELA ; HANNANI, DALIL ; MARTINS, ISABELLE ; MICHAUD, MICKAËL ; KEPP, OLIVER ; SUKKURWALA, ABDUL QADER ; VACCHELLI, ERIKA ; GALLUZZI, LORENZO ; ZITVOGEL, LAURENCE ; KROEMER, GUIDO . ATP-dependent recruitment, survival and differentiation of dendritic cell precursors in the tumor bed after anticancer chemotherapy. OncoImmunology , v. 2, p. e24568, 2013.

• 2012 MARTINS, ISABELLE ; MICHAUD, MICKAEL ; SUKKURWALA, ABDUL QADER ; ADJEMIAN, SANDY ; MA, YUTING ; SHEN, SHENSI ; KEPP, OLIVER ; MENGER, LAURIE ; VACCHELLI, ERIKA ; GALLUZZI, LORENZO ; ZITVOGEL, LAURENCE ; KROEMER, GUIDO . Premortem autophagy determines the immunogenicity of chemotherapy-induced cancer cell death. Autophagy (Georgetown, TX) , v. 8, p. 413-415, 2012.

• 2012 LADOIRE, SYLVAIN ; CHABA, KARIMAN ; MARTINS, ISABELLE ; SUKKURWALA, ABDUL QADER ; ADJEMIAN, SANDY ; MICHAUD, MICKAËL ; POIRIER-COLAME, VICHNOU ; ANDREIUOLO, FELIPE ; GALLUZZI, LORENZO ; WHITE, EILEEN ; ROSENFELDT, MATHIAS ; RYAN, KEVIN M. ; ZITVOGEL, LAURENCE ; KROEMER, GUIDO . Immunohistochemical detection of cytoplasmic LC3 puncta in human cancer specimens. Autophagy (Georgetown, TX) , v. 8, p. 1175-1184, 2012.

• 2012 VACCHELLI, ERIKA ; GALLUZZI, LORENZO ; ROUSSEAU, VANESSA ; RIGONI, ALICE ; TESNIERE, ANTOINE ; DELAHAYE, NICOLAS ; SCHLEMMER, FRE´DE´RIC ; MENGER, LAURIE ; SUKKURWALA, ABDUL QADER ; ADJEMIAN, SANDY ; MARTINS, ISABELLE ; MICHAUD, MICKAËL ; DUNANT, ARIANE ; KEPP, OLIVER ; BRAMBILLA, ELISABETH ; SORIA, JEAN-CHARLES ; ZITVOGEL, LAURENCE ; KROEMER, GUIDO . Loss-of-function alleles of P2RX7 and TLR4 fail to affect the response to chemotherapy in non-small cell lung cancer. OncoImmunology , v. 1, p. 271-278, 2012.

• 2012 MENGER, L. ; VACCHELLI, E. ; ADJEMIAN, S. ; MARTINS, I. ; MA, Y. ; SHEN, S. ; YAMAZAKI, T. ; SUKKURWALA, A. Q. ; MICHAUD, M. ; MIGNOT, G. ; SCHLEMMER, F. ; SULPICE, E. ; LOCHER, C. ; GIDROL, X. ; GHIRINGHELLI, F. ; MODJTAHEDI, N. ; GALLUZZI, L. ; ANDRE, F. ; ZITVOGEL, L. ; KEPP, O. ; KROEMER, G. . Cardiac Glycosides Exert Anticancer Effects by Inducing Immunogenic Cell Death. Science Translational Medicine , v. 4, p. 143ra99-143ra99, 2012.

• 2012 GALLUZZI, LORENZO VITALE, ILIO SENOVILLA, LAURA OLAUSSEN, KEN ANDRÉ PINNA, GUILLAUME EISENBERG, TOBIAS GOUBAR, AÏCHA MARTINS, ISABELLE MICHELS, JUDITH KRATASSIOUK, GUEORGUI CARMONA-GUTIERREZ, DIDAC SCOAZEC, MARIE VACCHELLI, ERIKA SCHLEMMER, FREDERIC KEPP, OLIVER SHEN, SHENSI TAILLER, MAXIMILIEN NISO-SANTANO, MIREIA MORSELLI, EUGENIA CRIOLLO, ALFREDO ADJEMIAN, SANDY JEMAÀ, MOHAMED CHABA, KARIMAN PAILLERET, CLAIRE MICHAUD, MICKAËL , et al. PIETROCOLA, FEDERICO TAJEDDINE, NICOLAS DE LA MOTTE ROUGE, THIBAULT ARAUJO, NATALIA MOROZOVA, NADYA ROBERT, THOMAS RIPOCHE, HUGUES COMMO, FREDERIC BESSE, BENJAMIN VALIDIRE, PIERRE FOURET, PIERRE ROBIN, ANGÉLIQUE DORVAULT, NICOLAS GIRARD, PHILIPPE GOUY, SÉBASTIEN PAUTIER, PATRICIA JÄGEMANN, NORA NICKEL, ANN-CHRISTIN MARSILI, SABRINA PACCARD, CAROLINE SERVANT, NICOLAS HUPÉ, PHILIPPE BEHRENS, CARMEN BEHNAM-MOTLAGH, PARVIZ KOHNO, KIMITOSHI CREMER, ISABELLE DAMOTTE, DIANE ALIFANO, MARCO MIDTTUN, IVIND UELAND, PER MAGNE LAZAR, VLADIMIR DESSEN, PHILIPPE ZISCHKA, HANS CHATELUT, ETIENNE CASTEDO, MARIA MADEO, FRANK BARILLOT, EMMANUEL THOMALE, JUERGEN WISTUBA, IGNACIO IVAN SAUTÈS-FRIDMAN, CATHERINE ZITVOGEL, LAURENCE SORIA, JEAN-CHARLES HAREL-BELLAN, ANNICK KROEMER, GUIDO ; Prognostic Impact of Vitamin B6 Metabolism in Lung Cancer. Cell Reports , v. 2, p. 257-269, 2012.

• 2012 SENOVILLA, L. VITALE, I. MARTINS, I. TAILLER, M. PAILLERET, C. MICHAUD, M. GALLUZZI, L. ADJEMIAN, S. KEPP, O. NISO-SANTANO, M. SHEN, S. MARINO, G. CRIOLLO, A. BOILEVE, A. JOB, B. LADOIRE, S. GHIRINGHELLI, F. SISTIGU, A. YAMAZAKI, T. RELLO-VARONA, S. LOCHER, C. POIRIER-COLAME, V. TALBOT, M. VALENT, A. BERARDINELLI, F. , et al. ANTOCCIA, A. CICCOSANTI, F. FIMIA, G. M. PIACENTINI, M. FUEYO, A. MESSINA, N. L. LI, M. CHAN, C. J. SIGL, V. POURCHER, G. RUCKENSTUHL, C. CARMONA-GUTIERREZ, D. LAZAR, V. PENNINGER, J. M. MADEO, F. LOPEZ-OTIN, C. SMYTH, M. J. ZITVOGEL, L. CASTEDO, M. KROEMER, G. ; An Immunosurveillance Mechanism Controls Cancer Cell Ploidy. Science (New York, N.Y.: Online) , v. 337, p. 1678-1684, 2012.

• 2012 SHEN, SHENSI ; NISO-SANTANO, MIREIA ; ADJEMIAN, SANDY ; TAKEHARA, TETSUO ; MALIK, SHOAIB AHMAD ; MINOUX, HERVÉ ; SOUQUERE, SYLVIE ; MARIÑO, GUILLERMO ; LACHKAR, SYLVIE ; SENOVILLA, LAURA ; GALLUZZI, LORENZO ; KEPP, OLIVER ; PIERRON, GÉRARD ; MAIURI, MARIA CHIARA ; HIKITA, HAYATO ; KROEMER, ROMANO ; KROEMER, GUIDO . Cytoplasmic STAT3 Represses Autophagy by Inhibiting PKR Activity. Molecular Cell , v. 48, p. 1-14, 2012.

• 2012 SENOVILLA, LAURA ; VACCHELLI, ERIKA ; GALON, JEROME ; ADJEMIAN, SANDY ; EGGERMONT, ALEXANDER ; FRIDMAN, WOLF HERVÉ ; SAUTÈS-FRIDMAN, CATHERINE ; MA, YUTING ; TARTOUR, ERIC ; ZITVOGEL, LAURENCE ; KROEMER, GUIDO ; GALLUZZI, LORENZO . Trial watch: Prognostic and predictive value of the immune infiltrate in cancer. OncoImmunology , v. 1, p. 1323-1343, 2012.

• KEPP, OLIVER ; MENGER, LAURIE ; VACCHELLI, ERIKA ; ADJEMIAN, SANDY ; MARTINS, ISABELLE ; MA, YUTING ; SUKKURWALA, ABDUL QADER ; MICHAUD, MICKAËL ; GALLUZZI, LORENZO ; ZITVOGEL, LAURENCE ; KROEMER, GUIDO . Anticancer activity of cardiac glycosides: At the frontier between cell-autonomous and immunological effects. OncoImmunology , v. 1, p. 1640-1642, 2012.

• 2011 MICHAUD, M. ; MARTINS, I. ; SUKKURWALA, A. Q. ; ADJEMIAN, S. ; MA, Y. ; PELLEGATTI, P. ; SHEN, S. ; KEPP, O. ; SCOAZEC, M. ; MIGNOT, G. ; RELLO-VARONA, S. ; TAILLER, M. ; MENGER, L. ; VACCHELLI, E. ; GALLUZZI, L. ; GHIRINGHELLI, F. ; DI VIRGILIO, F. ; ZITVOGEL, L. ; KROEMER, G. . Autophagy-Dependent Anticancer Immune Responses Induced by Chemotherapeutic Agents in Mice. Science (New York, N.Y.: Online) , v. 334, p. 1573-1577, 2011.

• 2011 KROEMER, G. ; ADJEMIAN, SANDY ; MICHAUD, M. ; MARTINS, I. ; KEPP, O ; SUKKURWALA, A. Q. ; MENGER, L ; VACCHELLI, E. ; MA, Y. ; ZITVOGEL, L . Contributions of immunogenic cell death to the efficacy of anticancer chemotherapy. Bull Mem Acad R Med Belg. , v. 166, p. 3, 2011.

• 2011 KEPP, O ; GALLUZZI, LORENZO ; MARTINS, I ; SCHLEMMER, F ; ADJEMIAN, S ; MICHAUD, MICKAEL ; SUKKURWALA, A. Q. ; MENGER, L ; ZITVOGEL, L ; KROEMER, G. . Molecular determinants of immunogenic cell death elicited by anticancer chemotherapy.. Cancer Metastasis Reviews (Print) , v. 30, p. 1, 2011.

• 2010 MARTINS, ISABELLE ; KEPP, OLIVER ; GALLUZZI, LORENZO ; SENOVILLA, LAURA ; SCHLEMMER, FREDERIC ; ADJEMIAN, SANDY ; MENGER, LAURIE ; MICHAUD, MICKAEL ; ZITVOGEL, LAURENCE ; KROEMER, GUIDO . Surface-exposed calreticulin in the interaction between dying cells and phagocytes. Annals of the New York Academy of Sciences , v. 1209, p. 77-82, 2010.

• 2010 MARTINS, I ; KEPP, O ; SCHLEMMER, F ; ADJEMIAN, S ; TAILLER, M ; SHEN, S ; MICHAUD, M ; MENGER, L ; GDOURA, A ; TAJEDDINE, N ; TESNIERE, A ; ZITVOGEL, L ; KROEMER, G . Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress. Oncogene (Basingstoke) , v. 30, p. 1147-1158, 2010.

• 2009 KEPP, OLIVER ; GALLUZZI, LORENZO ; GIORDANETTO, FABRIZIO ; TESNIERE, ANTOINE ; VITALE, ILIO ; MARTINS, ISABELLE ; SCHLEMMER, FREDERIC ; ADJEMIAN, SANDY ; ZITVOGEL, LAURENCE ; KROEMER, GUIDO . Disruption of the PP1/GADD34 complex induces calreticulin exposure. Cell Cycle (Georgetown, Tex.) , v. 8, p. 3971-3977, 2009.

• KEPP, OLIVER ; MARTINS, ISABELLE ; MENGER, LAURIE ; MICHAUD, MICKAËL ; Adjemian, Sandy ; SUKKURWALA, ABDUL QADER ; GALLUZZI, LORENZO ; KROEMER, GUIDO . Methods in Molecular Biology. 1. ed. Humana Press, 2013.

• MARTINS, ISABELLE ; KEPP, OLIVER ; MENGER, LAURIE ; Michaud, Mickäel ; Adjemian, Sandy ; SUKKURWALA, ABDUL QADER ; VACCHELLI, ERIKA ; GALLUZZI, LORENZO ; KROEMER, GUIDO . Methods in Molecular Biology. 1. ed. Humana Press, 2013.

• ADJEMIAN, S. . Intratumoral Recruitment and Differentiation of Antigen-Presenting Cells in Anticancer Chemotherapy. 2014. (Apresentação de Trabalho/Seminário).

Projetos de pesquisa

• 2013 - Atual

  Analysis of global gene expression regulated by the PRAME/EZH2 complex as a tool to discover new therapeutic targets against cancer, Descrição: Recentemente, trabalhando com células de pacientes com LMC, nosso grupo de pesquisa desvendou um novo mecanismo responsável por diminuir a expressão de TRAIL, um dos ligantes dos chamados receptores de morte , considerado uma das armas mais importantes que temos para o combate ao câncer (De Carvalho et al., 2011). Partindo-se da observação de um processo bem estabelecido em melanoma (Epping et al., 2005), avaliado como um dos mecanismos responsáveis por conferir vantagens de sobrevivência e/ou crescimento às células tumorais, nosso grupo identificou potenciais novos alvos para estratégias terapêuticas em LMC. Em melanoma, na presença de ácido retinóico, PRAME (preferentially expressed antigen of melanoma) em complexo com EZH2 (enhancer of zeste homolog 2) pode se ligar ao receptor de ácido retinóico, prevenindo a ativação de genes alvo desse receptor, pelo silenciamento epigenético mediado pela atividade histona metiltransferase de EZH2 (Epping et al., 2005). Em nosso trabalho, verificamos uma correlação inversa entre a expressão de PRAME e TRAIL, em células provenientes de pacientes com LMC (Carvalho et al., 2011). Além disto, observamos uma ligação de EZH2 à região promotora de TRAIL, dependente da presença de PRAME (De Carvalho et al., 2011). Finalmente, a inibição de PRAME ou EZH2 pela tecnologia de RNAi reativou a expressão de TRAIL, aumentando a sensibilidade das células ao tratamento com imatinibe (De Carvalho et al., 2011). É importante destacar que este mecanismo parece estar operando em diversos tipos de tumores, uma vez que análises in silico de experimentos envolvendo expressão gênica, realizadas através do Oncomine Research (www.oncomine.org), apontam para uma correlação significativa entre aumento da expressão de PRAME com baixa expressão de TRAIL em diversos tipos de tumores sólidos, como adenocarcinoma de pulmão, melanoma, carcinoma de mama, comparados aos seus respectivos tecidos normais (Beer et al., 2002); (Haqq et al., 2005); (Stearman et al., 2005); (Hoek et al., 2006); (Richardson et al., 2006). Apesar da clara implicação de TRAIL no modelo em questão, é factível que outras proteinas com papeis similares ou até maiores que TRAIL sejam reguladas por PRAME/EZH2; é de onde vem a fundamental necessidade de se investigar de maneira global, através de análise da expressão gênica por micro arranjos, quais genes (consequentemente quais vias bioquímicas) são modulados pela combinação de PRAME e EZH2, em linhagens celulares estabelecidas de pacientes com LMC, e qual o impacto desses possíveis genes no estado tumorigênico do modelo proposto.. , Situação: Em andamento; Natureza: Pesquisa. , Integrantes: Sandy ADJEMIAN PORTELA CATANI - Integrante / Sandy ADJEMIAN - Integrante / Gustavo P. Amarante-Mendes - Coordenador.

• 2013 - Atual

  Regulação da expressão gênica de FASL pela PGE2 em linfócitos T CD4+: papel do repressor transcricional ICER., Descrição: Os linfócitos T CD4+ orquestram a resposta imune adaptativa, auxiliando os macrófagos, os linfócitos T CD8+ e os linfócitos B na resposta mais eficiente frente a um antígeno. As etapas que caracterizam uma resposta imune adaptativa são: apresentação do antígeno aos linfócitos T pelas APCs (antigen-presenting cells), ativação e diferenciação dos linfócitos T em células efetoras e de memória, expansão clonal e morte celular para retorno à homeostasia. Esta morte celular na fase terminal da resposta imune, ocorre por apoptose através da morte celular induzida por ativação (AICD-activation-induced cell death) e morte autônoma de células T ativadas (ACAD-activated T cell autonomous death). O primeiro tipo de morte ocorre via receptor de morte FAS e sua interação com seu ligante, FASL. Dentro desse contexto, nosso grupo de pesquisa demonstrou que a PGE2, secretada por APCs, após estímulo com LPS, inibe a expressão de fasl em hibridomas de linfócitos T CD4+ (DO11.10), inibindo a morte dessas células por AICD. Tendo em vista que o mecanismo pelo qual a PGE2 inibe a expressão de fasl ainda não é conhecido, o presente trabalho tem como objetivo compreender o mecanismo molecular de atuação da PGE2 sobre os linfócitos T CD4+ na inibição gênica do FASL, tendo como hipótese o envolvimento do repressor transcricional ICER (induced cAMP early repressor), o qual se liga a sítios de ligação CRE (cAMP responsive elements) nos promotores gênicos.. , Situação: Em andamento; Natureza: Pesquisa. , Integrantes: Sandy ADJEMIAN PORTELA CATANI - Integrante / Sandy ADJEMIAN - Integrante / Gustavo P. Amarante-Mendes - Coordenador / Cristiane Naffah-de-Souza - Integrante.

• 2009 - 2012

  Essential factors for the success of immunogenic therapy, Descrição: Most of the cytotoxic agents used in cancer therapy are known to be immunosuppressive, because of their unspecific targeting of rapidly dividing cells, like tumor cells, but also cells of the immune system. However, radiotherapy, as well as some chemotherapeutic agents such as anthracyclines or oxaliplatine were reported to have immunostimulatory effects, thanks to their capacity to induce immunogenic tumor cell death. This type of cell death is characterized by the release of danger signals from the dying tumor cell, which will activate the immune system. As a first event, exposure of calreticulin from the dying tumor cell will act as an eat-me signal for dendritic cells. Once released, the nuclear protein HMGB1 will bind to TLR4, facilitating antigen processing and presentation. The dying tumor cells will also release ATP, which acts on P2X7 receptors and activates NLRP3 inflammasomme, leading to IL-1β release, necessary for IFN-γ- producing CD8+ T cells activation. Autophagy is a degradation process limiting genomic instability and cancer initiation. It can be induced after a stress of the endoplasmic reticulum (ER). ER-stress is also involved in calreticulin exposure during immunogenic cell death, so we aimed at understanding the role of autophagy in immunogenic cell death. We found that autophagy is required for the release of ATP after treatment with immunogenic chemotherapies. Moreover, we showed that ATP released from the dying cells is necessary for the recruitment of immune cells with inflammatory monocyte phenotype (CD11b+Ly6ChighLy6G-), as well as their precursors. ATP was also important for the differentiation of these inflammatory monocytes into dendritic cells. These CD11b+Ly6ChighLy6G- cells were efficient in presenting the tumor antigens to CD8+ T cells, and to induce a tumor-specific immune response. However, autophagy-deficient cells were not able to recuit dendritic cells or to induce CD8+ T cells activation. These studies showed the importance of autophagy in tumor-specific immune response, after treatment with immunogenic chemotherapies. We also reported that ATP is involved in the recruitment and differentiation of cells with inflammatory monocytes phenotype. Altogether, these results give new insights in the concept of immunogenic cell death.. , Situação: Concluído; Natureza: Pesquisa. , Integrantes: Sandy ADJEMIAN PORTELA CATANI - Integrante / Sandy ADJEMIAN - Integrante / MA, YUTING - Integrante / GUIDO KROEMER - Coordenador.

• 2009 - 2012

  Cardiac Glycosides Exert Anticancer Effects by Inducing Immunogenic Cell Death, Descrição: The efficacy of some anti-cancer agents, including anthracyclines and oxaliplatin is based on their capacity to induce immunogenic cell death (ICD) in tumor cells. This peculiar type of apoptosis is defined by a sequential emission of specific immunogenic signals from the dying tumor, which in their correct spatio-temporal appearance ignite a specific immune response against therapy resistant and dormant tumor (stem) cells. Thus the early membrane exposure of the ER-resident molecular chaperone calreticulin (CRT) constitutes a critical uptake signal for the engulfment of dying tumor cells by dendritic cells (DCs). Then, at later stages, the autophagy-dependent secretion of ATP and its binding to purinergic receptors on DCs activates the NLRP3 inflammasome. Subsequent release of IL-1 by DC triggers the polarization of IFN-γ producing CD8+ T cells. Finally, during secondary necrosis, the release of the pro-immunogenic high-mobility group box 1 (HMGB1) protein and its interaction with Toll like receptor 4 (TLR4) on DCs facilitates an optimal antigen presentation to T cells. Thus ICD contributes to the tumoricidal activity of chemotherapy and protecting the host from relapse. In order to identify thus far unknown inducers of ICD, a high content screening of compound libraries approved by the Food and Drug Administration (FDA) was conducted by means of robotized automated bioimaging combined with ICD biosensors allowing for the detection of CRT relocation, ATP secretion and HMGB1 release. This multiparametric approach led to the identification of cardiac glycosides (CGs), already well known for their preferential cytotoxic activity on cancer cells, as effective inducers of ICD. The hit compounds were validated by alternative methods in vitro, followed by a mechanistic study of GC induced ICD. Results indicated an on-target inhibition of the Na+/K+ ATPase subunit 1, which in turn interfered with the Ca2+-homeostasis of the target cell, an effect that could be mimicked by Ca2+ ionophores. We then showed in different mouse models that tumor cells killed with a combination of GC and non-immunogenic chemotherapy (cisplatin or mitomycin C) have the ability to immunize syngeneic mice against rechallenge with living cells. In addition the antineoplastic effects of these DNA damaging agents in vivo were increased by GCs in immunocompetent but not in immunodeficient mice. Finally, retrospective clinical analyses revealed that the administration of the GC digoxin during chemotherapy had a significant positive impact on overall survival in cohorts of breast, colorectal, head and neck, and hepatocellular carcinoma patients, especially when they were treated with agents other than anthracyclines and oxaliplatin.. , Situação: Concluído; Natureza: Pesquisa. , Integrantes: Sandy ADJEMIAN PORTELA CATANI - Integrante / Sandy ADJEMIAN - Integrante / KROEMER, G - Coordenador / Laurie Menger - Integrante.

• 2009 - 2012

  Autophagy : A New Modulator of Immunogenic Cell Death for Cancer Therapy, Descrição: In recent years it has been demonstrated that some chemotherapeutic agents such as anthracyclines or oxaliplatin can induce a type of tumor cell death that is immunogenic, implying that the patient s dying cancer cells serve as a therapeuticvaccine that stimulates an antitumor immune response, which in turn can control or eradicate residual cancer cells. Immunogenic cell death is characterized by the emission of danger signals from the dying tumor cell, which activate the immune system. At first the exposure of calreticulin, acts as an eat-me signal for dendritic cells (DCs). Once released, the nuclear protein HMGB1 binds to TLR4 on DCs, facilitating antigen processing and presentation. The dying tumor cells also releases ATP, which acts on P2X7 receptors on DCs and activates the NLRP3 inflammasome, leading to IL-1β release, necessary for IFN-γ-producing CD8+ T cell activation. Autophagy literally self-eating is a cellular process activated in response to various conditions of cellular stress, whereby cells can liberate energy resources via the degradation of proteins and organelles. Recently autophagy has been found activated in response to chemotherapy and in this project we aimed to determine the potential role of autophagy in immunogenic cell death. We found that autophagy isrequired for the release of ATP in response to immunochemotherapeutic treatment, as we observed that the knockdown of essential autophagy-related genes abolished its secretion. We observed that autophagy deficient cells treated with immunogenic cell death inducers failed to immunize mice against a re-challenge with living cells. Furthermore, autophagy deficient tumors growing on immunocompetent mice did not respond to systemic immunogenic treatment and continued proliferating in contrast to autophagy proficient tumors. We showed that autophagy deficient cells were neither able to recruit DCs into the tumor bed nor to activate CD8+ T cells. Conversely, the inhibition of extracellular ATP degrading enzymes increased extracellular ATP concentrations in autophagy deficient tumors, which reestablished the recruitment of immune cells into the tumor bed, and restored chemotherapeutic responses in autophagy-deficient cancers. Altogether, this study showed the importance of autophagy in tumor-specific immune response after treatment with chemotherapy, thus giving new insights into the concept of immunogenic cell death.. , Situação: Concluído; Natureza: Pesquisa. , Integrantes: Sandy ADJEMIAN PORTELA CATANI - Integrante / Sandy ADJEMIAN - Integrante / MARTINS, I - Integrante / KROEMER, G - Coordenador / SUKKURWALA, A. Q. - Integrante / MICKAEL MICHAUD - Integrante.

• 2008 - 2009

  BH3-only proteins and cell death, Descrição: As proteínas BH3-only são membros da família Bcl-2 que desempenham um papel importante na regulação da via intrínseca da apoptose. BNIP3, BNIP3L e Beclin-1 pertencem a família BH3-only, mas seu papel na apoptose é controverso e estudos recentes tem sugerido sua implicação na autofagia. O objetivo deste projeto foi de compreender o papel de BNIP3, BNIP3L e Beclin-1 na regulação da apoptose e da autofagia. Para isso nós construímos um sistema de expressão condicional em vetores adenovirais para super-expressar estes genes em diferentes modelos de câncer.. , Situação: Concluído; Natureza: Pesquisa. , Integrantes: Sandy ADJEMIAN PORTELA CATANI - Integrante / Sandy ADJEMIAN - Integrante / Peter T. DANIEL - Coordenador.

• 2007 - 2007

  Role of Angiotensine Type II receptor in proliferation and differentiation of undifferentiated rat myoblast cells, Descrição: O receptor de angiotensina tipo II é super expresso após um infarto no miocárdio e varios estudos afirmam que esta super-expressão leva a proteção cardíaca. Para mostrar a ação deste receptor sobre células mioblásticas indiferenciadas de rato, o receptor de angiotensina II foi estimulado nestas células. O efeito sobre a proliferação e diferenciação foi então avaliado.. , Situação: Concluído; Natureza: Pesquisa. , Integrantes: Sandy ADJEMIAN PORTELA CATANI - Integrante / Sandy ADJEMIAN - Integrante / Jun Li - Coordenador.

• 2005 - 2005

  Cloning, Sequencing and analysis of the coding sequence of retroviral integrase after mutagenesis, Descrição: Após mutagênese direta do Cas-Br-E MuLV, um modelo murino do retrovírus HIV, a produção do vírus foi completamente inibida. Para estudar o impacto desta mutagênese no gene da integrase e verificar a especificidade da mutação induzida, o gene da integrase foi clonado e depois seqüenciado.. , Situação: Concluído; Natureza: Pesquisa. , Integrantes: Sandy ADJEMIAN PORTELA CATANI - Integrante / Sandy ADJEMIAN - Integrante / Elsy EDOUARD - Coordenador.