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Joan Massagué

Bernardo Queralt, Elisabet Cuyàs, Joaquim Bosch-Barrera, Anna Massaguer, Rafael de Llorens, Begoña Martin-Castillo, Joan Brunet, Ramon Salazar, Javier A Menendez
KRAS mutations are an established predictor of lack of response to EGFR-targeted therapies in patients with metastatic colorectal cancer (mCRC). However, little is known about the role of the rarer NRAS mutations as a mechanism of primary resistance to the anti-EGFR monoclonal antibody cetuximab in wild-type KRAS mCRC. Using isogenic mCRC cells with a heterozygous knock-in of the NRAS activating mutation Q61K, we aimed to elucidate the mechanism(s) by which mutant NRAS blocks cetuximab from inhibiting mCRC growth...
September 12, 2016: Oncotarget
Helena Pomares, Claudia M Palmeri, Daniel Iglesias-Serret, Cristina Moncunill-Massaguer, José Saura-Esteller, Sonia Núñez-Vázquez, Enric Gamundi, Montserrat Arnan, Sara Preciado, Fernando Albericio, Rodolfo Lavilla, Gabriel Pons, Eva M González-Barca, Ana M Cosialls, Joan Gil
Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins (PHBs). In this study, the pro-apoptotic effect of fluorizoline was assessed in two cell lines and 21 primary samples from patients with debut of acute myeloid leukemia (AML). Fluorizoline induced apoptosis in AML cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespectively of patients' clinical or genetic features. In addition, fluorizoline inhibited the clonogenic capacity and induced differentiation of AML cells...
August 17, 2016: Oncotarget
Qing Chen, Adrienne Boire, Xin Jin, Manuel Valiente, Ekrem Emrah Er, Alejandro Lopez-Soto, Leni S Jacob, Ruzeen Patwa, Hardik Shah, Ke Xu, Justin R Cross, Joan Massagué
Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF)...
May 26, 2016: Nature
Srinivas Malladi, Danilo G Macalinao, Xin Jin, Lan He, Harihar Basnet, Yilong Zou, Elisa de Stanchina, Joan Massagué
Metastasis frequently develops years after the removal of a primary tumor, from a minority of disseminated cancer cells that survived as latent entities through unknown mechanisms. We isolated latency competent cancer (LCC) cells from early stage human lung and breast carcinoma cell lines and defined the mechanisms that suppress outgrowth, support long-term survival, and maintain tumor-initiating potential in these cells during the latent metastasis stage. LCC cells show stem-cell-like characteristics and express SOX2 and SOX9 transcription factors, which are essential for their survival in host organs under immune surveillance and for metastatic outgrowth under permissive conditions...
March 24, 2016: Cell
Charles J David, Yun-Han Huang, Mo Chen, Jie Su, Yilong Zou, Nabeel Bardeesy, Christine A Iacobuzio-Donahue, Joan Massagué
TGF-β signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-β mediator Smad4. We show that TGF-β induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-β-sensitive PDA cells, EMT becomes lethal by converting TGF-β-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis...
February 25, 2016: Cell
Swarnali Acharyya, Joan Massague
It is becoming increasingly clear that leukocytes dynamically regulate cancer progression and metastasis, and among leukocytes, granulocytic cells abundantly accumulate in metastatic organs; however, their function in metastasis remains controversial. In a recent report in Nature, Wculek and Malanchi clarify the role of mature neutrophils as mediators of metastatic initiation and provide a targeted approach to prevent the pro-metastatic activity of neutrophils in breast cancer models.
March 2016: Cell Research
Joan Massagué, Anna C Obenauf
Metastasis is the main cause of death in people with cancer. To colonize distant organs, circulating tumour cells must overcome many obstacles through mechanisms that we are only now starting to understand. These include infiltrating distant tissue, evading immune defences, adapting to supportive niches, surviving as latent tumour-initiating seeds and eventually breaking out to replace the host tissue. They make metastasis a highly inefficient process. However, once metastases have been established, current treatments frequently fail to provide durable responses...
January 21, 2016: Nature
Anna C Obenauf, Joan Massagué
The clinical manifestation of metastasis in a vital organ is the final stage of cancer progression and the main culprit of cancer related mortality. Once established, metastasis is devastating, yet only a small proportion of the cancer cells that leave a tumor succeed at infiltrating, surviving, and ultimately overtaking a distant organ. The bottlenecks that challenge cancer cells in newly invaded microenvironments are organ specific and consequently demand distinct mechanisms for metastatic colonization. Here we review the metastatic traits that allow cancer cells to colonize distinct organ sites...
September 1, 2015: Trends in Cancer
Marta Soler, Eduard Figueras, Joan Serrano-Plana, Marta González-Bártulos, Anna Massaguer, Anna Company, Ma Ángeles Martínez, Jaroslav Malina, Viktor Brabec, Lidia Feliu, Marta Planas, Xavi Ribas, Miquel Costas
The conjugation of redox-active complexes that can function as chemical nucleases to cationic tetrapeptides is pursued in this work in order to explore the expected synergistic effect between these two elements in DNA oxidative cleavage. Coordination complexes of biologically relevant first row metal ions, such as Zn(II) or Cu(II), containing the tetradentate ligands 1,4-dimethyl-7-(2-pyridylmethyl)-1,4,7-triazacyclononane ((Me2)PyTACN) and (2S,2S')-1,1'-bis(pyrid-2-ylmethyl)-2,2'-bipyrrolidine ((S,S')-BPBP) have been linked to a cationic LKKL tetrapeptide sequence...
November 16, 2015: Inorganic Chemistry
Cristina Moncunill-Massaguer, José Saura-Esteller, Alba Pérez-Perarnau, Claudia Mariela Palmeri, Sonia Núñez-Vázquez, Ana M Cosialls, Diana M González-Gironès, Helena Pomares, Anne Korwitz, Sara Preciado, Fernando Albericio, Rodolfo Lavilla, Gabriel Pons, Thomas Langer, Daniel Iglesias-Serret, Joan Gil
We previously described diaryl trifluorothiazoline compound 1a (hereafter referred to as fluorizoline) as a first-in-class small molecule that induces p53-independent apoptosis in a wide range of tumor cell lines. Fluorizoline directly binds to prohibitin 1 and 2 (PHBs), two proteins involved in the regulation of several cellular processes, including apoptosis. Here we demonstrate that fluorizoline-induced apoptosis is mediated by PHBs, as cells depleted of these proteins are highly resistant to fluorizoline treatment...
December 8, 2015: Oncotarget
Leni S Jacob, Sakari Vanharanta, Anna C Obenauf, Mono Pirun, Agnes Viale, Nicholas D Socci, Joan Massagué
Several experimental models faithfully recapitulate many important facets of human metastatic disease. Here, we have performed whole-exome sequencing in five widely used experimental metastasis models that were independently derived through in vivo selection from heterogeneous human cancer cell lines. In addition to providing an important characterization of these model systems, our study examines the genetic evolution of metastatic phenotypes. We found that in vivo selected highly metastatic cell populations showed little genetic divergence from the corresponding parental population...
September 15, 2015: Cancer Research
Maria J Macias, Pau Martin-Malpartida, Joan Massagué
Smad transcription factors are central to the signal transduction pathway that mediates the numerous effects of the transforming growth factor β (TGF-β) superfamily of cytokines in metazoan embryo development as well as in adult tissue regeneration and homeostasis. Although Smad proteins are conserved, recent genome-sequencing projects have revealed their sequence variation in metazoan evolution, human polymorphisms, and cancer. Structural studies of Smads bound to partner proteins and target DNA provide a framework for understanding the significance of these evolutionary and pathologic sequence variations...
June 2015: Trends in Biochemical Sciences
Anna C Obenauf, Yilong Zou, Andrew L Ji, Sakari Vanharanta, Weiping Shu, Hubing Shi, Xiangju Kong, Marcus C Bosenberg, Thomas Wiesner, Neal Rosen, Roger S Lo, Joan Massagué
Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression...
April 16, 2015: Nature
Alba Pérez-Perarnau, Sara Preciado, Claudia Mariela Palmeri, Cristina Moncunill-Massaguer, Daniel Iglesias-Serret, Diana M González-Gironès, Miriam Miguel, Satoki Karasawa, Satoshi Sakamoto, Ana M Cosialls, Camila Rubio-Patiño, José Saura-Esteller, Rosario Ramón, Laia Caja, Isabel Fabregat, Gabriel Pons, Hiroshi Handa, Fernando Albericio, Joan Gil, Rodolfo Lavilla
A new class of small molecules, with an unprecedented trifluorothiazoline scaffold, were synthesized and their pro-apoptotic activity was evaluated. With an EC50 in the low micromolar range, these compounds proved to be potent inducers of apoptosis in a broad spectrum of tumor cell lines, regardless of the functional status of p53. Fast structure-activity relationship studies allowed the preparation of the strongest apoptosis-inducing candidate. Using a high performance affinity purification approach, we identified prohibitins 1 and 2, key proteins involved in the maintenance of cell viability, as the targets for these compounds...
September 15, 2014: Angewandte Chemie
Lisa Sevenich, Robert L Bowman, Steven D Mason, Daniela F Quail, Franck Rapaport, Benelita T Elie, Edi Brogi, Priscilla K Brastianos, William C Hahn, Leslie J Holsinger, Joan Massagué, Christina S Leslie, Johanna A Joyce
Metastasis remains the most common cause of death in most cancers, with limited therapies for combating disseminated disease. While the primary tumour microenvironment is an important regulator of cancer progression, it is less well understood how different tissue environments influence metastasis. We analysed tumour-stroma interactions that modulate organ tropism of brain, bone and lung metastasis in xenograft models. We identified a number of potential modulators of site-specific metastasis, including cathepsin S as a regulator of breast-to-brain metastasis...
September 2014: Nature Cell Biology
Sakari Vanharanta, Christina B Marney, Weiping Shu, Manuel Valiente, Yilong Zou, Aldo Mele, Robert B Darnell, Joan Massagué
The mechanisms through which cancer cells lock in altered transcriptional programs in support of metastasis remain largely unknown. Through integrative analysis of clinical breast cancer gene expression datasets, cell line models of breast cancer progression, and mutation data from cancer genome resequencing studies, we identified RNA binding motif protein 47 (RBM47) as a suppressor of breast cancer progression and metastasis. RBM47 inhibited breast cancer re-initiation and growth in experimental models. Transcriptome-wide HITS-CLIP analysis revealed widespread RBM47 binding to mRNAs, most prominently in introns and 3'UTRs...
2014: ELife
Mònica Morales, Enrique J Arenas, Jelena Urosevic, Marc Guiu, Esther Fernández, Evarist Planet, Robert Bryn Fenwick, Sonia Fernández-Ruiz, Xavier Salvatella, David Reverter, Arkaitz Carracedo, Joan Massagué, Roger R Gomis
In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis...
July 2014: EMBO Molecular Medicine
Thordur Oskarsson, Eduard Batlle, Joan Massagué
Metastasis is powered by disseminated cancer cells that re-create a full-fledged tumor in unwelcoming tissues, away from the primary site. How cancer cells moving from a tumor into the circulation manage to infiltrate distant organs and initiate metastatic growth is of interest to cancer biologists and clinical oncologists alike. Recent findings have started to define the sources, phenotypic properties, hosting niches, and signaling pathways that support the survival, self-renewal, dormancy, and reactivation of cancer cells that initiate metastasis: metastatic stem cells...
March 6, 2014: Cell Stem Cell
Manuel Valiente, Anna C Obenauf, Xin Jin, Qing Chen, Xiang H-F Zhang, Derek J Lee, Jamie E Chaft, Mark G Kris, Jason T Huse, Edi Brogi, Joan Massagué
Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth...
February 27, 2014: Cell
Marko Stankic, Svetlana Pavlovic, Yvette Chin, Edi Brogi, David Padua, Larry Norton, Joan Massagué, Robert Benezra
ID genes are required for breast cancer colonization of the lungs, but the mechanism remains poorly understood. Here, we show that Id1 expression induces a stem-like phenotype in breast cancer cells while retaining epithelial properties, contrary to the notion that cancer stem-like properties are inextricably linked to the mesenchymal state. During metastatic colonization, Id1 induces a mesenchymal-to-epithelial transition (MET), specifically in cells whose mesenchymal state is dependent on the Id1 target protein Twist1, but not at the primary site, where this state is controlled by the zinc finger protein Snail1...
December 12, 2013: Cell Reports
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