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Caja, Laia
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Publications (10 of 24) Show all publications
Bellomo, C., Caja, L., Fabregat, I., Mikulits, W., Kardassis, D., Heldin, C.-H. & Moustakas, A. (2018). Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma. Cell Death and Differentiation, 25(5), 885-903
Open this publication in new window or tab >>Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
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2018 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 25, no 5, p. 885-903Article in journal (Refereed) Published
Abstract [en]

Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor β (TGFβ) and liver X receptor α (LXRα) pathways. TGFβ is known to promote cytostatic and pro-apoptotic responses in HCC, and to facilitate mesenchymal differentiation. We here demonstrate that stimulation of the nuclear LXRα receptor system by physiological and clinically useful agonists controls the HCC response to TGFβ. Specifically, LXRα activation antagonizes the mesenchymal, reactive oxygen species and pro-apoptotic responses to TGFβ and the mesenchymal transcription factor Snail mediates this crosstalk. In contrast, LXRα activation and TGFβ cooperate in enforcing cytostasis in HCC, which preserves their epithelial features. LXRα influences Snail expression transcriptionally, acting on the Snail promoter. These findings propose that clinically used LXR agonists may find further application to the treatment of aggressive, mesenchymal HCCs, whose progression is chronically dependent on autocrine or paracrine TGFβ.

National Category
Medical and Health Sciences Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-339262 (URN)10.1038/s41418-017-0021-3 (DOI)000431770600007 ()29230000 (PubMedID)
Funder
Swedish Cancer Society, CAN 2012/438; CAN 2015/438; CAN 2016/445; CAN 2012/1186Swedish Research Council, K2013-66X-14936-10-5; 2015-02757
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-06-29Bibliographically approved
Caja, L., Tzavlaki, K., Dadras, M. S., Tan, E.-J., Hatem, G., Maturi, N. P., . . . Moustakas, A. (2018). Snail regulates BMP and TGF beta pathways to control the differentiation status of glioma-initiating cells. Oncogene, 37(19), 2515-2531
Open this publication in new window or tab >>Snail regulates BMP and TGF beta pathways to control the differentiation status of glioma-initiating cells
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2018 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, no 19, p. 2515-2531Article in journal (Refereed) Published
Abstract [en]

Glioblastoma multiforme is a brain malignancy characterized by high heterogeneity, invasiveness, and resistance to current therapies, attributes related to the occurrence of glioma stem cells (GSCs). Transforming growth factor beta (TGF beta) promotes self-renewal and bone morphogenetic protein (BMP) induces differentiation of GSCs. BMP7 induces the transcription factor Snail to promote astrocytic differentiation in GSCs and suppress tumor growth in vivo. We demonstrate that Snail represses stemness in GSCs. Snail interacts with SMAD signaling mediators, generates a positive feedback loop of BMP signaling and transcriptionally represses the TGFB1 gene, decreasing TGF beta 1 signaling activity. Exogenous TGF beta 1 counteracts Snail function in vitro, and in vivo promotes proliferation and re-expression of Nestin, confirming the importance of TGFB1 gene repression by Snail. In conclusion, novel insight highlights mechanisms whereby Snail differentially regulates the activity of the opposing BMP and TGF beta pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-355463 (URN)10.1038/s41388-018-0136-0 (DOI)000431873400005 ()29449696 (PubMedID)
Funder
Swedish Research Council, K2013-66X-14936-10-5Swedish Research Council, 2015-02757
Note

Andra och tredje författare delar andra författarskapet.

Available from: 2018-06-29 Created: 2018-06-29 Last updated: 2018-06-29Bibliographically approved
Bellomo, C., Caja, L. & Moustakas, A. (2016). Transforming growth factor beta as regulator of cancer stemness and metastasis. British Journal of Cancer, 115(7), 761-769
Open this publication in new window or tab >>Transforming growth factor beta as regulator of cancer stemness and metastasis
2016 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 7, p. 761-769Article, review/survey (Refereed) Published
Abstract [en]

Key elements of cancer progression towards metastasis are the biological actions of cancer stem cells and stromal cells in the tumour microenvironment. Cross-communication between tumour and stromal cells is mediated by secreted cytokines, one of which, the transforming growth factor beta (TGF beta), regulates essentially every cell within the malignant tissue. In this article, we focus on the actions of TGF beta on cancer stem cells, cancer-associated fibroblasts and immune cells that assist the overall process of metastatic dissemination. We aim at illustrating intricate connections made by various cells in the tumour tissue and which depend on the action of TGF beta.

Keywords
cancer-associated fibroblast, cancer stem cell, metastasis, immune suppression, transforming growth factor beta, tumour invasiveness
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-309834 (URN)10.1038/bjc.2016.255 (DOI)000384576100001 ()27537386 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilEU, FP7, Seventh Framework Programme
Available from: 2016-12-08 Created: 2016-12-07 Last updated: 2017-11-29Bibliographically approved
Caja, L. P., Bellomo, C. & Moustakas, A. (2015). Transforming growth factor beta and bone morphogenetic protein actions in brain tumors. FEBS Letters, 589(14), 1588-1597
Open this publication in new window or tab >>Transforming growth factor beta and bone morphogenetic protein actions in brain tumors
2015 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 589, no 14, p. 1588-1597Article, review/survey (Refereed) Published
Abstract [en]

Members of the transforming growth factor beta (TGF-beta) family are implicated in the biology of several cancers. Here we focus on malignancies of the brain and examine the TGF beta and the bone morphogenetic protein (BMP) signaling branches of the family. These pathways exhibit context-dependent actions during tumorigenesis, acting either as tumor suppressors or as pro-tumorigenic agents. In the brain, the TGF-beta s associate with oncogenic development and progression to the more malignant state. Inversely, the BMPs suppress tumorigenic potential by acting as agents that induce tumor cell differentiation. The latter has been best demonstrated in grade IV astrocytomas, otherwise known as glioblastoma multiforme. We discuss how the actions of TGF-beta s and BMPs on cancer stem cells may explain their effects on tumor progression, and try to highlight intricate mechanisms that may link tumor cell differentiation to invasion. The focus on TGF-beta and BMP and their actions in brain malignancies provides a rich territory for mechanistic understanding of tumor heterogeneity and suggests ways for improved therapeutic intervention, currently being addressed by clinical trials.

Keywords
Bone morphogenetic protein, Brain, Cancer, Differentiation, Glioma, Transforming growth factor beta
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-257522 (URN)10.1016/j.febslet.2015.04.058 (DOI)000355635900010 ()
Available from: 2015-07-03 Created: 2015-07-03 Last updated: 2017-12-04Bibliographically approved
Crosas-Molist, E., Meirelles, T., López-Luque, J., Serra-Peinado, C., Selva, J., Caja, L., . . . Egea, G. (2015). Vascular smooth muscle cell phenotypic changes in patients with Marfan syndrome. Arteriosclerosis, Thrombosis and Vascular Biology, 35(4), 960-972
Open this publication in new window or tab >>Vascular smooth muscle cell phenotypic changes in patients with Marfan syndrome
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2015 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 35, no 4, p. 960-972Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Marfan's syndrome is characterized by the formation of ascending aortic aneurysms resulting from altered assembly of extracellular matrix microfibrils and chronic tissue growth factor (TGF)-β signaling. TGF-β is a potent regulator of the vascular smooth muscle cell (VSMC) phenotype. We hypothesized that as a result of the chronic TGF-β signaling, VSMC would alter their basal differentiation phenotype, which could facilitate the formation of aneurysms. This study explores whether Marfan's syndrome entails phenotypic alterations of VSMC and possible mechanisms at the subcellular level.

APPROACH AND RESULTS: Immunohistochemical and Western blotting analyses of dilated aortas from Marfan patients showed overexpression of contractile protein markers (α-smooth muscle actin, smoothelin, smooth muscle protein 22 alpha, and calponin-1) and collagen I in comparison with healthy aortas. VSMC explanted from Marfan aortic aneurysms showed increased in vitro expression of these phenotypic markers and also of myocardin, a transcription factor essential for VSMC-specific differentiation. These alterations were generally reduced after pharmacological inhibition of the TGF-β pathway. Marfan VSMC in culture showed more robust actin stress fibers and enhanced RhoA-GTP levels, which was accompanied by increased focal adhesion components and higher nuclear localization of myosin-related transcription factor A. Marfan VSMC and extracellular matrix measured by atomic force microscopy were both stiffer than their respective controls.

CONCLUSIONS: In Marfan VSMC, both in tissue and in culture, there are variable TGF-β-dependent phenotypic changes affecting contractile proteins and collagen I, leading to greater cellular and extracellular matrix stiffness. Altogether, these alterations may contribute to the known aortic rigidity that precedes or accompanies Marfan's syndrome aneurysm formation.

Keywords
RhoA, TGF-β, actin, aortic aneurysms, aortic stiffness, extracellular matrix, focal adhesion, myocardin
National Category
Medical and Health Sciences Biological Sciences
Identifiers
urn:nbn:se:uu:diva-339265 (URN)10.1161/ATVBAHA.114.304412 (DOI)25593132 (PubMedID)
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-02-15Bibliographically approved
Pérez-Perarnau, A., Preciado, S., Palmeri, C. M., Moncunill-Massaguer, C., Iglesias-Serret, D., González-Gironès, D. M., . . . Lavilla, R. (2014). A trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins. Angewandte Chemie International Edition, 53(38), 10150-10154
Open this publication in new window or tab >>A trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins
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2014 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 53, no 38, p. 10150-10154Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
antitumor agents, drug discovery, fluorine, heterocycles, medicinal chemistry
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-339266 (URN)10.1002/anie.201405758 (DOI)25196378 (PubMedID)
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-02-15Bibliographically approved
Moreno-Càceres, J., Caja, L., Mainez, J., Mayoral, R., Martín-Sanz, P., Moreno-Vicente, R., . . . Fabregat, I. (2014). Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17. Cell Death and Disease, 5, Article ID e1326.
Open this publication in new window or tab >>Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17
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2014 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 5, article id e1326Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-beta (TGF-β) plays a dual role in hepatocytes, inducing both pro- and anti-apoptotic responses, whose balance decides cell fate. Survival signals are mediated by the epidermal growth factor receptor (EGFR) pathway, which is activated by TGF-β in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-β receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1 is required for TGF-β-induced anti-apoptotic signals, but the molecular mechanism is not fully understood yet. In this work, we show that immortalized Cav1(-/-) hepatocytes were more sensitive to the pro-apoptotic effects induced by TGF-β, showing a higher activation of caspase-3, higher decrease in cell viability and prolonged increase through time of intracellular reactive oxygen species (ROS). These results were coincident with attenuation of TGF-β-induced survival signals in Cav1(-/-) hepatocytes, such as AKT and ERK1/2 phosphorylation and NFκ-B activation. Transactivation of the EGFR pathway by TGF-β was impaired in Cav1(-/-) hepatocytes, which correlated with lack of activation of TACE/ADAM17, the metalloprotease responsible for the shedding of EGFR ligands. Reconstitution of Cav1 in Cav1(-/-) hepatocytes rescued wild-type phenotype features, both in terms of EGFR transactivation and TACE/ADAM17 activation. TACE/ADAM17 was localized in detergent-resistant membrane (DRM) fractions in Cav1(+/+) cells, which was not the case in Cav1(-/-) cells. Disorganization of lipid rafts after treatment with cholesterol-binding agents caused loss of TACE/ADAM17 activation after TGF-β treatment. In conclusion, in hepatocytes, Cav1 is required for TGF-β-mediated activation of the metalloprotease TACE/ADAM17 that is responsible for shedding of EGFR ligands and activation of the EGFR pathway, which counteracts the TGF-β pro-apoptotic effects. Therefore, Cav1 contributes to the pro-tumorigenic effects of TGF-β in liver cancer cells.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-339267 (URN)10.1038/cddis.2014.294 (DOI)25032849 (PubMedID)
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-02-15Bibliographically approved
Bertran, E., Crosas-Molist, E., Sancho, P., Caja, L., Lopez-Luque, J., Navarro, E., . . . Fabregat, I. (2013). Overactivation of the TGF-β pathway confers a mesenchymal-like phenotype and CXCR4-dependent migratory properties to liver tumor cells. Hepatology, 58(6), 2032-44
Open this publication in new window or tab >>Overactivation of the TGF-β pathway confers a mesenchymal-like phenotype and CXCR4-dependent migratory properties to liver tumor cells
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2013 (English)In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 58, no 6, p. 2032-44Article in journal (Refereed) Published
Abstract [en]

UNLABELLED: Transforming growth factor-beta (TGF-β) is an important regulatory suppressor factor in hepatocytes. However, liver tumor cells develop mechanisms to overcome its suppressor effects and respond to this cytokine by inducing other processes, such as the epithelial-mesenchymal transition (EMT), which contributes to tumor progression and dissemination. Recent studies have placed chemokines and their receptors at the center not only of physiological cell migration but also of pathological processes, such as metastasis in cancer. In particular, CXCR4 and its ligand, stromal cell-derived factor 1α (SDF-1α) / chemokine (C-X-C motif) ligand 12 (CXCL12) have been revealed as regulatory molecules involved in the spreading and progression of a variety of tumors. Here we show that autocrine stimulation of TGF-β in human liver tumor cells correlates with a mesenchymal-like phenotype, resistance to TGF-β-induced suppressor effects, and high expression of CXCR4, which is required for TGF-β-induced cell migration. Silencing of the TGF-β receptor1 (TGFBR1), or its specific inhibition, recovered the epithelial phenotype and attenuated CXCR4 expression, inhibiting cell migratory capacity. In an experimental mouse model of hepatocarcinogenesis (diethylnitrosamine-induced), tumors showed increased activation of the TGF-β pathway and enhanced CXCR4 levels. In human hepatocellular carcinoma tumors, high levels of CXCR4 always correlated with activation of the TGF-β pathway, a less differentiated phenotype, and a cirrhotic background. CXCR4 concentrated at the tumor border and perivascular areas, suggesting its potential involvement in tumor cell dissemination.

CONCLUSION: A crosstalk exists among the TGF-β and CXCR4 pathways in liver tumors, reflecting a novel molecular mechanism that explains the protumorigenic effects of TGF-β and opens new perspectives for tumor therapy.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-339268 (URN)10.1002/hep.26597 (DOI)23813475 (PubMedID)
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-02-15Bibliographically approved
Savary, K., Caglayan, D., Caja, L., Tzavlaki, K., Bin Nayeem, S., Bergström, T., . . . Moustakas, A. (2013). Snail depletes the tumorigenic potential of glioblastoma. Oncogene, 32(47), 5409-5420
Open this publication in new window or tab >>Snail depletes the tumorigenic potential of glioblastoma
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2013 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 47, p. 5409-5420Article in journal (Refereed) Published
Abstract [en]

Glioblastoma multiforme (GBM) is an aggressive brain malignancy characterized by high heterogeneity and invasiveness. It is increasingly accepted that the refractory feature of GBM to current therapies stems from the existence of few tumorigenic cells that sustain tumor growth and spreading, the so-called glioma-initiating cells (GICs). Previous studies showed that cytokines of the bone morphogenetic protein (BMP) family induce differentiation of the GICs, and thus act as tumor suppressors. Molecular pathways that explain this behavior of BMP cytokines remain largely elusive. Here, we show that BMP signaling induces Smad-dependent expression of the transcriptional regulator Snail in a rapid and sustained manner. Consistent with its already established promigratory function in other cell types, we report that Snail silencing decreases GBM cell migration. Consequently, overexpression of Snail increases GBM invasiveness in a mouse xenograft model. Surprisingly, we found that Snail depletes the GBM capacity to form gliomaspheres in vitro and to grow tumors in vivo, both of which are important features shared by GICs. Thus Snail, acting downstream of BMP signaling, dissociates the invasive capacity of GBM cells from their tumorigenic potential.

Keywords
BMP, glioblastoma multiforme, glioma initiating cells, invasiveness, Snail
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-182944 (URN)10.1038/onc.2013.67 (DOI)000327177600004 ()23524585 (PubMedID)
Available from: 2012-10-19 Created: 2012-10-19 Last updated: 2018-01-12Bibliographically approved
Coppotelli, G., Mughal, N., Callegari, S., Sompallae, R., Caja Puigsubira, L., Luijsterburg, M. S., . . . Masucci, M. G. (2013). The Epstein-Barr virus nuclear antigen-1 reprograms transcription by mimicry of high mobility group A proteins. Nucleic Acids Research, 41(5), 2950-2962
Open this publication in new window or tab >>The Epstein-Barr virus nuclear antigen-1 reprograms transcription by mimicry of high mobility group A proteins
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2013 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 41, no 5, p. 2950-2962Article in journal (Refereed) Published
Abstract [en]

Viral proteins reprogram their host cells by hijacking regulatory components of protein networks. Here we describe a novel property of the Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA1) that may underlie the capacity of the virus to promote a global remodeling of chromatin architecture and cellular transcription. We found that the expression of EBNA1 in transfected human and mouse cells is associated with decreased prevalence of heterochromatin foci, enhanced accessibility of cellular DNA to micrococcal nuclease digestion and decreased average length of nucleosome repeats, suggesting de-protection of the nucleosome linker regions. This is a direct effect of EBNA1 because targeting the viral protein to heterochromatin promotes large-scale chromatin decondensation with slow kinetics and independent of the recruitment of adenosine triphosphate-dependent chromatin remodelers. The remodeling function is mediated by a bipartite Gly-Arg rich domain of EBNA1 that resembles the AT-hook of High Mobility Group A (HMGA) architectural transcription factors. Similar to HMGAs, EBNA1 is highly mobile in interphase nuclei and promotes the mobility of linker histone H1, which counteracts chromatin condensation and alters the transcription of numerous cellular genes. Thus, by regulating chromatin compaction, EBNA1 may reset cellular transcription during infection and prime the infected cells for malignant transformation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-197881 (URN)10.1093/nar/gkt032 (DOI)000318062600021 ()23358825 (PubMedID)
Available from: 2013-04-05 Created: 2013-04-05 Last updated: 2017-12-06Bibliographically approved
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