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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
Albert Gandioso, Anna Massaguer, Núria Villegas, Cándida Salvans, Dani Sánchez, Isabelle Brun-Heath, Vicente Marchán, Modesto Orozco, Montserrat Terrazas
Despite the broad applicability of the Huisgen cycloaddition reaction, the click functionalization of RNAs with peptides still remains a challenge. Here we describe a straightforward method for the click functionalization of siRNAs with peptides of different sizes and complexities. Among them, a promising peptide carrier for the selective siRNA delivery into HER2+ breast cancer cell lines has been reported.
February 20, 2017: Chemical Communications: Chem Comm
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
Albert Gandioso, Marc Cano, Anna Massaguer, Vicente Marchán
We describe for the first time the synthesis and photochemical properties of a coumarin-caged cyclic RGD peptide and demonstrate that uncaging can be efficiently performed with biologically compatible green light. This was accomplished by using a new dicyanocoumarin derivative (DEAdcCE) for the protection of the carboxyl function at the side chain of the aspartic acid residue, which was selected on the basis of Fmoc-tBu SPPS compatibility and photolysis efficiency. The shielding effect of a methyl group incorporated in the coumarin derivative near the ester bond linking both moieties in combination with the use of acidic additives such as HOBt or Oxyma during the basic Fmoc-removal treatment were found to be very effective for minimizing aspartimide-related side reactions...
December 2, 2016: Journal of Organic Chemistry
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
M Soler, M González-Bártulos, E Figueras, A Massaguer, L Feliu, M Planas, X Ribas, M Costas
Peptide conjugates incorporating the N-based ligands (Me2)PyTACN or (S,S')-BPBP at the N- or the C-terminus of the cell-penetrating peptide were synthesized (PyTACN-BP16 (), BP16-PyTACN (), BPBP-BP16 (), and BP16-BPBP ()). Metal binding peptides bearing at the N-terminus the ligand, an additional Lys and a β-Ala were also prepared (PyTACN-βAK-BP16 () and BPBP-βAK-BP16 ()). Moreover, taking into account the clathrin-dependent endocytic mechanism of , the enzymatic cleavable tetrapeptide Gly-Phe-Leu-Gly was incorporated between the ligand and the N- or C-terminus of (BPBP-GFLG-BP16 () and BP16-GLFG-BPBP ())...
April 26, 2016: Organic & Biomolecular Chemistry
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
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
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
Clara Panosa, Humphrey Fonge, Montserrat Ferrer-Batallé, Javier A Menéndez, Anna Massaguer, Rafael De Llorens, Raymond M Reilly
INTRODUCTION: EGFt is a truncated form of human epidermal growth factor (hEGF) that is non-biologically active but retains binding and internalization into EGFR-positive cells. Our aim was to compare EGFt and hEGF for delivery of (111)In to human breast cancer (BC) cells and tumors and evaluate its cytotoxicity against EGFR-positive BC cells, mediated by the Auger electron emissions of (111)In. METHODS: The binding, internalization and nuclear localization of EGFt and hEGF in MDA-MB-468 human BC cells were first assessed by confocal fluorescence microscopy...
December 2015: Nuclear Medicine and Biology
Marta González-Bártulos, Clara Aceves-Luquero, Jamal Qualai, Olaf Cussó, M Angeles Martínez, Silvia Fernández de Mattos, Javier A Menéndez, Priam Villalonga, Miquel Costas, Xavi Ribas, Anna Massaguer
Differential redox homeostasis in normal and malignant cells suggests that pro-oxidant-induced upregulation of cellular reactive oxygen species (ROS) should selectively target cancer cells without compromising the viability of untransformed cells. Consequently, a pro-oxidant deviation well-tolerated by nonmalignant cells might rapidly reach a cell-death threshold in malignant cells already at a high setpoint of constitutive oxidative stress. To test this hypothesis, we took advantage of a selected number of amine-pyridine-based Fe(II) complexes that operate as efficient and robust oxidation catalysts of organic substrates upon reaction with peroxides...
2015: PloS One
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