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Massagué J

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
Evyenia Shaili, Marta Fernández-Giménez, Savina Rodríguez-Astor, Albert Gandioso, Lluís Sandín, Carlos García-Vélez, Anna Massaguer, Guy J Clarkson, Julie A Woods, Peter J Sadler, Vicente Marchán
A photoactivatable platinum(IV) complex, trans,trans,trans-[Pt(N3 )2 (OH)(succ)(py)2 ] (succ=succinylate, py=pyridine), has been conjugated to guanidinoneomycin to study the effect of this guanidinum-rich compound on the photoactivation, intracellular accumulation and phototoxicity of the pro-drug. Surprisingly, trifluoroacetic acid treatment causes the replacement of an azido ligand and the axial hydroxide ligand by trifluoroacetate, as shown by NMR spectroscopy, MS and X-ray crystallography. Photoactivation of the platinum-guanidinoneomycin conjugate in the presence of 5'-guanosine monophosphate (5'-GMP) led to the formation of trans-[Pt(N3 )(py)2 (5'-GMP)](+) , as does the parent platinum(IV) complex...
December 7, 2015: Chemistry: a European Journal
Albert Gandioso, Evyenia Shaili, Anna Massaguer, Gerard Artigas, Alejandro González-Cantó, Julie A Woods, Peter J Sadler, Vicente Marchán
A new anticancer agent based on the conjugation of a photoactivatable Pt(IV) pro-drug to a cyclic RGD-containing peptide is described. Upon visible light irradiation, phototoxicity was induced preferentially in SK-MEL-28 melanoma cancer cells overexpressing αVβ3 integrin compared to control DU-145 human prostate carcinoma cells.
June 4, 2015: Chemical Communications: Chem Comm
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
L Cavero-Roig, Á Díaz-Conradi, A Negre-Loscertales, A Ferrero-Rosanas, A Salvador-Valle, S Burch-Piñol, O Urraca-Martínez, J Massaguer-Cabrera
INTRODUCTION: To describe the ophthalmological conditions seen in children adopted internationally by Spanish families, and to assess the influence of the world region of origin and the preadoption period of institutional care on these conditions. MATERIAL AND METHODS: A descriptive, observational, cross-sectional study was conducted on 232 children divided into 4 groups according to world region of origin: Group 1, eastern Europe (n=95); Group 2, Asia (n=95); Group 3, Central and South America (n=26); and Group 4, Africa (n=16)...
May 2015: Anales de Pediatría: Publicación Oficial de la Asociación Española de Pediatría (A.E.P.)
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
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
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
Nancy E Hynes, Philip W Ingham, Wendell A Lim, Christopher J Marshall, Joan Massagué, Tony Pawson
The past few years have marked significant anniversaries in signal transduction, including the identification of classic growth factors and morphogens, the notion of protein modification through phosphorylation and the characterization of protein interaction domains. Here, six researchers reflect on the context in which these discoveries were made, and how our concept of cell signalling has evolved during the past three decades.
June 2013: Nature Reviews. Molecular Cell Biology
Sakari Vanharanta, Weiping Shu, Fabienne Brenet, A Ari Hakimi, Adriana Heguy, Agnes Viale, Victor E Reuter, James J-D Hsieh, Joseph M Scandura, Joan Massagué
Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome...
January 2013: Nature Medicine
Eric Aragón, Nina Goerner, Qiaoran Xi, Tiago Gomes, Sheng Gao, Joan Massagué, Maria J Macias
Transforming growth factor (TGF)-β and BMP signaling is mediated by Smads 1-5 (R-Smads and Co-Smads) and inhibited by Smad7, a major hub of regulation of TGF-β and BMP receptors by negative feedback and antagonistic signals. The transcription coactivator YAP and the E3 ubiquitin ligases Smurf1/2 and Nedd4L target R-Smads for activation or degradation, respectively. Pairs of WW domain in these regulators bind PY motifs and adjacent CDK/MAPK and GSK3 phosphorylation sites in R-Smads in a selective and regulated manner...
October 10, 2012: Structure
Flavia Barragán, Dolors Carrion-Salip, Irene Gómez-Pinto, Alejandro González-Cantó, Peter J Sadler, Rafael de Llorens, Virtudes Moreno, Carlos González, Anna Massaguer, Vicente Marchán
Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl(2)(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η(6)-bip)Os(4-CO(2)-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η(6)-p-cym)RuCl(dap)](+) (p-cym = p-cymene) (5), and [(η(6)-p-cym)RuCl(imidazole-CO(2)H)(PPh(3))](+) (6), were synthesized by using a solid-phase approach. Conjugates 3-5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution...
September 19, 2012: Bioconjugate Chemistry
Qiaoran Xi, Zhanxin Wang, Alexia-Ileana Zaromytidou, Xiang H-F Zhang, Lai-Fong Chow-Tsang, Jing X Liu, Hyesoo Kim, Afsar Barlas, Katia Manova-Todorova, Vesa Kaartinen, Lorenz Studer, Willie Mark, Dinshaw J Patel, Joan Massagué
Specific chromatin marks keep master regulators of differentiation silent yet poised for activation by extracellular signals. We report that nodal TGF-β signals use the poised histone mark H3K9me3 to trigger differentiation of mammalian embryonic stem cells. Nodal receptors induce the formation of companion Smad4-Smad2/3 and TRIM33-Smad2/3 complexes. The PHD-Bromo cassette of TRIM33 facilitates binding of TRIM33-Smad2/3 to H3K9me3 and H3K18ac on the promoters of mesendoderm regulators Gsc and Mixl1. The crystal structure of this cassette, bound to histone H3 peptides, illustrates that PHD recognizes K9me3, and Bromo binds an adjacent K18ac...
December 23, 2011: Cell
Xin Lu, Euphemia Mu, Yong Wei, Sabine Riethdorf, Qifeng Yang, Min Yuan, Jun Yan, Yuling Hua, Benjamin J Tiede, Xuemin Lu, Bruce G Haffty, Klaus Pantel, Joan Massagué, Yibin Kang
Breast cancer patients often develop locoregional or distant recurrence years after mastectomy. Understanding the mechanism of metastatic recurrence after dormancy is crucial for improving the cure rate for breast cancer. Here, we characterize a bone metastasis dormancy model to show that aberrant expression of vascular cell adhesion molecule 1 (VCAM-1), in part dependent on the activity of the NF-κB pathway, promotes the transition from indolent micrometastasis to overt metastasis. By interacting with the cognate receptor integrin α4β1, VCAM-1 recruits monocytic osteoclast progenitors and elevates local osteoclast activity...
December 13, 2011: Cancer Cell
Feng Li, Olga V Glinskii, Jianjun Zhou, Landon S Wilson, Stephen Barnes, Douglas C Anthony, Vladislav V Glinsky
Brain is a common site of breast cancer metastasis associated with significant neurologic morbidity, decreased quality of life, and greatly shortened survival. However, the molecular and cellular mechanisms underpinning brain colonization by breast carcinoma cells are poorly understood. Here, we used 2D-DIGE (Difference in Gel Electrophoresis) proteomic analysis followed by LC-tandem mass spectrometry to identify the proteins differentially expressed in brain-targeting breast carcinoma cells (MB231-Br) compared with parental MDA-MB-231 cell line...
2011: PloS One
Thordur Oskarsson, Swarnali Acharyya, Xiang H-F Zhang, Sakari Vanharanta, Sohail F Tavazoie, Patrick G Morris, Robert J Downey, Katia Manova-Todorova, Edi Brogi, Joan Massagué
We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell-derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)...
July 2011: Nature Medicine
Eric Aragón, Nina Goerner, Alexia-Ileana Zaromytidou, Qiaoran Xi, Albert Escobedo, Joan Massagué, Maria J Macias
When directed to the nucleus by TGF-β or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, and of ubiquitin ligases Smurf1 and Nedd4L for Smad destruction. Here we demonstrate that there is an order of events-Smad activation first and destruction later-and that it is controlled by a switch in the recognition of Smad phosphoserines by WW domains in their binding partners...
June 15, 2011: Genes & Development
Kim J Png, Mitsukuni Yoshida, Xiang H-F Zhang, Weiping Shu, Hyeseung Lee, Andreas Rimner, Timothy A Chan, Elizabeth Comen, Viktor P Andrade, Seok Won Kim, Tari A King, Clifford A Hudis, Larry Norton, James Hicks, Joan Massagué, Sohail F Tavazoie
Post-transcriptional regulators have emerged as robust effectors of metastasis and display deregulated expression through unknown mechanisms. Here, we reveal that the human microRNA-335 locus undergoes genetic deletion and epigenetic promoter hypermethylation in every metastatic derivative obtained from independent patients' malignant cell populations. Genetic deletion of miR-335 is a common event in human breast cancer, is enriched for in breast cancer metastases, and also correlates with ovarian cancer recurrence...
February 1, 2011: Genes & Development
Jun-ichi Tamura, Tomomi Nakamura-Yamamoto, Yuko Nishimura, Shuji Mizumoto, Jun Takahashi, Kazuyuki Sugahara
Betaglycan, also known as TGF-β type III receptor, is a membrane-anchored proteoglycan, which has two glycosaminoglycan (GAG) attachment sites (López-Casillas, F.; Payne, H. M.; Andres, J. L.; Massagué, J. J.Cell Biol.1994, 124, 557-568). Chondroitin sulfate (CS) or heparan sulfate (HS) can attach to the first site, Ser(535), whereas only CS attaches to the second, Ser(546). Although the mechanism behind the assembly of CS and HS is not fully understood, it has been reported that the assembly of HS requires not only a cluster of acidic residues but also hydrophobic residues located near the Ser-Gly attachment sites (Esko, J...
October 13, 2010: Carbohydrate Research
Ann Richmond
Coverage on: Shields, J.D., Kourtis, I.C., Tomei, A.A., Roberts, J.M. & Swartz,M.A. (2010). Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science. E Pub, March 25, 2010; and Kim, M.Y., Oskarsson, T., Acharyya, S.,Nguyen, D.X., Zhang, X.H., Norton, L. & Massague, J. (2009). Tumor self-seeding by circulating cancer cells. Cell, 139,1315-1326.
June 2010: Pigment Cell & Melanoma Research
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