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Joan Massagué

Karuna Ganesh, Joan Massagué
Immune checkpoint therapy can induce durable remissions, but many tumors demonstrate resistance. In a recent issue of Nature, Mariathasan et al. (2018) and Tauriello et al. (2018) identify stromal TGF-β signaling as a determinant of immune exclusion. Combination TGF-β inhibition and immunotherapy induces complete responses in mouse models.
April 17, 2018: Immunity
Charles J David, Joan Massagué
Few cell signals match the impact of the transforming growth factor-β (TGFβ) family in metazoan biology. TGFβ cytokines regulate cell fate decisions during development, tissue homeostasis and regeneration, and are major players in tumorigenesis, fibrotic disorders, immune malfunctions and various congenital diseases. The effects of the TGFβ family are mediated by a combinatorial set of ligands and receptors and by a common set of receptor-activated mothers against decapentaplegic homologue (SMAD) transcription factors, yet the effects can differ dramatically depending on the cell type and the conditions...
April 11, 2018: Nature Reviews. Molecular Cell Biology
Pau Martin-Malpartida, Marta Batet, Zuzanna Kaczmarska, Regina Freier, Tiago Gomes, Eric Aragón, Yilong Zou, Qiong Wang, Qiaoran Xi, Lidia Ruiz, Angela Vea, José A Márquez, Joan Massagué, Maria J Macias
Smad transcription factors activated by TGF-β or by BMP receptors form trimeric complexes with Smad4 to target specific genes for cell fate regulation. The CAGAC motif has been considered as the main binding element for Smad2/3/4, whereas Smad1/5/8 have been thought to preferentially bind GC-rich elements. However, chromatin immunoprecipitation analysis in embryonic stem cells showed extensive binding of Smad2/3/4 to GC-rich cis-regulatory elements. Here, we present the structural basis for specific binding of Smad3 and Smad4 to GC-rich motifs in the goosecoid promoter, a nodal-regulated differentiation gene...
December 12, 2017: Nature Communications
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
No abstract text is available yet for this article.
April 6, 2017: Nature
Adrienne Boire, Yilong Zou, Jason Shieh, Danilo G Macalinao, Elena Pentsova, Joan Massagué
We molecularly dissected leptomeningeal metastasis, or spread of cancer to the cerebrospinal fluid (CSF), which is a frequent and fatal condition mediated by unknown mechanisms. We selected lung and breast cancer cell lines for the ability to infiltrate and grow in CSF, a remarkably acellular, mitogen-poor metastasis microenvironment. Complement component 3 (C3) was upregulated in four leptomeningeal metastatic models and proved necessary for cancer growth within the leptomeningeal space. In human disease, cancer cells within the CSF produced C3 in correlation with clinical course...
March 9, 2017: Cell
Tapas R Nayak, Chrysafis Andreou, Anton Oseledchyk, Warren D Marcus, Hing C Wong, Joan Massagué, Moritz F Kircher
Here we demonstrate a novel application of 'surface enhanced resonance Raman scattering nanoparticles' (SERRS NPs) for imaging breast cancer lung metastases with much higher precision than currently feasible. A breast cancer lung metastasis mouse model was established by intravenous injection of LM2 cells. These mice were intravenously administered SERRS NPs conjugated with ALT-836, an anti-tissue factor (TF) monoclonal antibody, and subjected to Raman imaging to visualize the expression of TF both in vivo and ex vivo...
January 19, 2017: Nanoscale
Qiong Wang, Yilong Zou, Sonja Nowotschin, Sang Yong Kim, Qing V Li, Chew-Li Soh, Jie Su, Chao Zhang, Weiping Shu, Qiaoran Xi, Danwei Huangfu, Anna-Katerina Hadjantonakis, Joan Massagué
In this study, we outline a regulatory network that involves the p53 tumor suppressor family and the Wnt pathway acting together with the TGF-β pathway in mesendodermal differentiation of mouse and human embryonic stem cells. Knockout of all three members, p53, p63, and p73, shows that the p53 family is essential for mesendoderm specification during exit from pluripotency in embryos and in culture. Wnt3 and its receptor Fzd1 are direct p53 family target genes in this context, and induction of Wnt signaling by p53 is critical for activation of mesendodermal differentiation genes...
January 5, 2017: Cell Stem Cell
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...
December 13, 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...
October 4, 2016: Oncotarget
Qing Chen, Adrienne Boire, Xin Jin, Manuel Valiente, Ekrem Emrah Er, Alejandro Lopez-Soto, Leni 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
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