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Publications (10 of 30) Show all publications
Lopez-Luque, J., Bertran, E., Crosas-Molist, E., Maiques, O., Malfettone, A., Caja, L., . . . Fabregat, I. (2019). Downregulation of Epidermal Growth Factor Receptor in hepatocellular carcinoma facilitates Transforming Growth Factor-beta-induced epithelial to amoeboid transition. Cancer Letters, 464(Nov), 15-24
Open this publication in new window or tab >>Downregulation of Epidermal Growth Factor Receptor in hepatocellular carcinoma facilitates Transforming Growth Factor-beta-induced epithelial to amoeboid transition
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2019 (English)In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 464, no Nov, p. 15-24Article in journal (Refereed) Published
Abstract [en]

The Epidermal Growth Factor Receptor (EGFR) and the Transforming Growth Factor-beta (TGF-beta) are key regulators of hepatocarcinogenesis. Targeting EGFR was proposed as a promising therapy; however, poor success was obtained in human hepatocellular carcinoma (HCC) clinical trials. Here, we describe how EGFR is frequently downregulated in HCC patients while TGF-beta is upregulated. Using 2D/3D cellular models, we show that after EGFR loss, TGF-beta is more efficient in its pro-migratory and invasive effects, inducing epithelial to amoeboid transition. EGFR knock-down promotes loss of cell-cell and cell-to-matrix adhesion, favouring TGF-beta-induced actomyosin contractility and acquisition of an amoeboid migratory phenotype. Moreover, TGF-beta upregulates RHOC and CDC42 after EGFR silencing, promoting Myosin II in amoeboid cells. Importantly, low EGFR combined with high TGFBI or RHOC/CDC42 levels confer poor patient prognosis. In conclusion, this work reveals a new tumour suppressor function for EGFR counteracting TGF-beta-mediated epithelial to amoeboid transitions in HCC, supporting a rational for targeting the TGF-beta pathway in patients with low EGFR expression. Our work also highlights the relevance of epithelial to amoeboid transition in human tumours and the need to better target this process in the clinic.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2019
Keywords
Liver, Migration, Adhesion, Matrix, Myosin II
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-395562 (URN)10.1016/j.canlet.2019.08.011 (DOI)000487572200003 ()31465839 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, PITN-GA-2012-316549
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-10-21Bibliographically approved
Zhang, Y., Valsala Madhavan Unnithan, R., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., . . . Olsson, A.-K. (2019). TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells. The FASEB Journal, 33(7), 7822-7832
Open this publication in new window or tab >>TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells
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2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 7, p. 7822-7832Article in journal (Refereed) Published
Abstract [en]

Platelets can promote several stages of the metastatic process and thus contribute to malignant progression. As an example, platelets promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study, we show that tumor necrosis factor receptor-associated factor (TRAF) family member-associated NF-kappa B activator (TANK)-binding kinase 1 (TBK1) is a previously unknown mediator of platelet-induced EMT in mammary carcinoma cells. Coculture of 2 mammary carcinoma cell lines, Ep5 from mice and MCF10A(MII) from humans, with isolated platelets induced morphologic as well as molecular changes characteristic of EMT, which was paralleled with activation of TBK1. TBK1 depletion using small interfering RNA impaired platelet-induced EMT in both Ep5 and MCF10A(MII) cells. Furthermore, platelet-induced activation of the NF-kappa B subunit p65 was suppressed after TBK1 knockdown, demonstrating that TBK1 mediates platelet-induced NF-kappa B signaling and EMT. Using an in vivo metastasis assay, we found that depletion of TBK1 from mammary carcinoma cells during in vitro preconditioning with platelets subsequently suppressed the formation of lung metastases in mice. Altogether, these results suggest that TBK1 contributes to tumor invasiveness and may be a driver of metastatic spread in breast cancer.-Zhang, Y., Unnithan, R. V. M., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., Cedervall, J., Olsson, A.-K. TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells.

Keywords
platelets, cancer, TBK1, NF-kappa B, metastasis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-392047 (URN)10.1096/fj.201801936RRR (DOI)000476234700004 ()30912981 (PubMedID)
Funder
Swedish Research Council, 2016-03036Swedish Cancer Society, CAN 2017/522Swedish Society of Medicine, SLS-683851
Note

Ragaseema Valsala Madhavan Unnithan and Anahita Hamidi contributed equally to this work.

Jessica Cedervall and Anna-Karin Olsson contributed equally to this work.

Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-09-10Bibliographically approved
Papoutsoglou, P., Tsubakihara, Y., Caja, L., Morén, A., Pallis, P., Ameur, A., . . . Moustakas, A. (2019). The TGFB2-AS1 lncRNA Regulates TGF-beta Signaling by Modulating Corepressor Activity. Cell reports, 28(12), 3182-3198.ell
Open this publication in new window or tab >>The TGFB2-AS1 lncRNA Regulates TGF-beta Signaling by Modulating Corepressor Activity
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 28, no 12, p. 3182-3198.ellArticle in journal (Refereed) Published
Abstract [en]

Molecular processes involving lncRNAs regulate cell function. By applying transcriptomics, we identify lncRNAs whose expression is regulated by transforming growth factor beta (TGF-beta). Upon silencing individual lncRNAs, we identify several that regulate TGF-beta signaling. Among these lncRNAs, TGFB2-antisense RNA1 (TGFB2-AS1) is induced by TGF-beta through Smad and protein kinase pathways and resides in the nucleus. Depleting TGFB2-AS1 enhances TGF-beta/Smad-mediated transcription and expression of hallmark TGF-beta-target genes. Increased dose of TGFB2-AS1 reduces expression of these genes, attenuates TGF-beta-induced cell growth arrest, and alters BMP and Wnt pathway gene profiles. Mechanistically, TGFB2-AS1, mainly via its 3' terminal region, binds to the EED adaptor of the Polycomb repressor complex 2 (PRC2), promoting repressive histone H3K27me(3) modifications at TGF-beta-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity partially rescues TGFB2-AS1-mediated gene repression. Thus, the TGF-beta-induced TGFB2-AS1 lncRNA exerts inhibitory functions on TGF-beta/BMP signaling output, supporting auto-regulatory negative feedback that balances TGF-beta/BMP-mediated responses.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-395306 (URN)10.1016/j.celrep.2019.08.028 (DOI)000486389400014 ()31533040 (PubMedID)
Funder
Swedish Cancer Society, CAN2015/438Swedish Research Council, K2013-66X-14936-10-5Swedish Research Council, 2015-02757EU, European Research Council, 787472
Available from: 2019-10-18 Created: 2019-10-18 Last updated: 2019-10-18Bibliographically approved
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: 2018-12-03Bibliographically 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: 2018-12-03Bibliographically approved
Caja, L., Dituri, F., Mancarella, S., Caballero-Diaz, D., Moustakas, A., Giannelli, G. & Fabregat, I. (2018). TGF-β and the Tissue Microenvironment: Relevance in Fibrosis and Cancer. International Journal of Molecular Sciences, 19(5), Article ID E1294.
Open this publication in new window or tab >>TGF-β and the Tissue Microenvironment: Relevance in Fibrosis and Cancer
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2018 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 5, article id E1294Article, review/survey (Refereed) Published
Abstract [en]

Transforming growth factor-β (TGF-β) is a cytokine essential for the induction of the fibrotic response and for the activation of the cancer stroma. Strong evidence suggests that a strong cross-talk exists among TGF-β and the tissue extracellular matrix components. TGF-β is stored in the matrix as part of a large latent complex bound to the latent TGF-β binding protein (LTBP) and matrix binding of latent TGF-β complexes, which is required for an adequate TGF-β function. Once TGF-β is activated, it regulates extracellular matrix remodelling and promotes a fibroblast to myofibroblast transition, which is essential in fibrotic processes. This cytokine also acts on other cell types present in the fibrotic and tumour microenvironment, such as epithelial, endothelial cells or macrophages and it contributes to the cancer-associated fibroblast (CAF) phenotype. Furthermore, TGF-β exerts anti-tumour activity by inhibiting the host tumour immunosurveillance. Aim of this review is to update how TGF-β and the tissue microenvironment cooperate to promote the pleiotropic actions that regulate cell responses of different cell types, essential for the development of fibrosis and tumour progression. We discuss recent evidences suggesting the use of TGF-β chemical inhibitors as a new line of defence against fibrotic disorders or cancer.

Keywords
TGF-β, fibrosis, cancer, HCC, microenvironment, CAF, hepatic stellate cells, extracellular matrix, galunisertib
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-366814 (URN)10.3390/ijms19051294 (DOI)000435297000030 ()29701666 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, PITN-GA-2012-316549European Regional Development Fund (ERDF)Swedish Research Council, K2013-66X-14936-10-5Swedish Cancer Society, CAN2015/438
Note

WoS title: TGF-beta and the Tissue Microenvironment: Relevance in Fibrosis and Cancer

Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2018-12-03Bibliographically approved
Papoutsoglou, P., Tsubakihara, Y., Caja, L., Pallis, P., Ameur, A., Heldin, C.-H. & Moustakas, A. (2018). The TGFB2-AS1 lncRNA regulates TGFβ signaling by modulating corepressor activity.
Open this publication in new window or tab >>The TGFB2-AS1 lncRNA regulates TGFβ signaling by modulating corepressor activity
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2018 (English)Article in journal (Refereed) Submitted
Abstract [en]

LncRNAs regulate cell function through many physiological processes. We have identified lncRNAs whose expression is regulated by transforming growth factor β (TGFβ), by a transcriptomic screen. We focused on TGFB2-antisense RNA1 (TGFB2-AS1), which was induced by TGFβ through Smad and protein kinase pathways, and exhibited predominantly nuclear localization. Depleting TGFB2-AS1 enhanced TGFβ/Smad-mediated transcription and expression of the TGFβ-target genes FN1 and SERPINE1. Overexpression of TGFB2-AS1 reduced expression of these genes, attenuated TGFβ-induced cell growth arrest, and altered BMP and Wnt pathway gene profiles. Mechanistically, TGFB2-AS1 mainly via its 3’ terminal region, bound to EED, an adaptor of the Polycomb repressor complex 2 (PRC2), promoting repressive histone H3K27me3 modifications at TGFβ-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity, partially rescued TGFB2-AS1 mediated gene repression. Our observations support the notion that TGFB2-AS1 is a TGFβ-induced lncRNA with inhibitory functions on TGFβ and BMP pathways output, constituting an auto-regulatory negative feedback mechanism that balances TGFβ- and BMP-mediated responses.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-363700 (URN)
Available from: 2018-10-20 Created: 2018-10-20 Last updated: 2018-12-03
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: 2018-12-03Bibliographically 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: 2018-12-03Bibliographically 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: 2018-12-03Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-8786-8763

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