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Article ; Online: MAGI1, a Scaffold Protein with Tumor Suppressive and Vascular Functions

Janine Wörthmüller / Curzio Rüegg

Cells, Vol 10, Iss 1494, p

2021 Volume 1494

Abstract: MAGI1 is a cytoplasmic scaffolding protein initially identified as a component of cell-to-cell contacts stabilizing cadherin-mediated cell–cell adhesion in epithelial and endothelial cells. Clinical-pathological and experimental evidence indicates that ... ...

Abstract	MAGI1 is a cytoplasmic scaffolding protein initially identified as a component of cell-to-cell contacts stabilizing cadherin-mediated cell–cell adhesion in epithelial and endothelial cells. Clinical-pathological and experimental evidence indicates that MAGI1 expression is decreased in some inflammatory diseases, and also in several cancers, including hepatocellular carcinoma, colorectal, cervical, breast, brain, and gastric cancers and appears to act as a tumor suppressor, modulating the activity of oncogenic pathways such as the PI3K/AKT and the Wnt/β-catenin pathways. Genomic mutations and other mechanisms such as mechanical stress or inflammation have been described to regulate MAGI1 expression. Intriguingly, in breast and colorectal cancers, MAGI1 expression is induced by non-steroidal anti-inflammatory drugs (NSAIDs), suggesting a role in mediating the tumor suppressive activity of NSAIDs. More recently, MAGI1 was found to localize at mature focal adhesion and to regulate integrin-mediated adhesion and signaling in endothelial cells. Here, we review MAGI1′s role as scaffolding protein, recent developments in the understanding of MAGI1 function as tumor suppressor gene, its role in endothelial cells and its implication in cancer and vascular biology. We also discuss outstanding questions about its regulation and potential translational implications in oncology.
Keywords	breast cancer ; tumor suppressor ; PTEN ; PI3K/AKT ; Wnt ; focal adhesions ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Targeting myeloid-derived suppressor cells in combination with tumor cell vaccination predicts anti-tumor immunity and breast cancer dormancy

Reza Mehdizadeh / Seyed Peyman Shariatpanahi / Bahram Goliaei / Curzio Rüegg

Scientific Reports, Vol 13, Iss 1, Pp 1-

an in silico experiment

2023 Volume 11

Abstract: Abstract Among the different breast cancer subsets, triple-negative breast cancer (TNBC) has the worst prognosis and limited options for targeted therapies. Immunotherapies are emerging as novel treatment opportunities for TNBC. However, the surging ... ...

Abstract	Abstract Among the different breast cancer subsets, triple-negative breast cancer (TNBC) has the worst prognosis and limited options for targeted therapies. Immunotherapies are emerging as novel treatment opportunities for TNBC. However, the surging immune response elicited by immunotherapies to eradicate cancer cells can select resistant cancer cells, which may result in immune escape and tumor evolution and progression. Alternatively, maintaining the equilibrium phase of the immune response may be advantageous for keeping a long-term immune response in the presence of a small-size residual tumor. Myeloid-derived suppressor cells (MDSCs) are activated, expanded, and recruited to the tumor microenvironment by tumor-derived signals and can shape a pro-tumorigenic micro-environment by suppressing the innate and adaptive anti-tumor immune responses. We recently proposed a model describing immune-mediated breast cancer dormancy instigated by a vaccine consisting of dormant, immunogenic breast cancer cells derived from the murine 4T1 TNBC-like cell line. Strikingly, these 4T1-derived dormant cells recruited fewer MDSCs compared to aggressive 4T1 cells. Recent experimental studies demonstrated that inactivating MDSCs has a profound impact on reconstituting immune surveillance against the tumor. Here, we developed a deterministic mathematical model for simulating MDSCs depletion from mice bearing aggressive 4T1 tumors resulting in immunomodulation. Our computational simulations indicate that a vaccination strategy with a small number of tumor cells in combination with MDSC depletion can elicit an effective immune response suppressing the growth of a subsequent challenge with aggressive tumor cells, resulting in sustained tumor dormancy. The results predict a novel therapeutic opportunity based on the induction of effective anti-tumor immunity and tumor dormancy.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Crosstalk between FAK and Wnt Signaling Pathways in Cancer and Its Therapeutic Implication

Janine Wörthmüller / Curzio Rüegg

International Journal of Molecular Sciences, Vol 21, Iss 9107, p

2020 Volume 9107

Abstract: Focal adhesion kinase (FAK) and Wnt signaling pathways are important contributors to tumorigenesis in several cancers. While most results come from studies investigating these pathways individually, there is increasing evidence of a functional crosstalk ... ...

Abstract	Focal adhesion kinase (FAK) and Wnt signaling pathways are important contributors to tumorigenesis in several cancers. While most results come from studies investigating these pathways individually, there is increasing evidence of a functional crosstalk between both signaling pathways during development and tumor progression. A number of FAK–Wnt interactions are described, suggesting an intricate, context-specific, and cell type-dependent relationship. During development for instance, FAK acts mainly upstream of Wnt signaling; and although in intestinal homeostasis and mucosal regeneration Wnt seems to function upstream of FAK signaling, FAK activates the Wnt/β-catenin signaling pathway during APC-driven intestinal tumorigenesis. In breast, lung, and pancreatic cancers, FAK is reported to modulate the Wnt signaling pathway, while in prostate cancer, FAK is downstream of Wnt. In malignant mesothelioma, FAK and Wnt show an antagonistic relationship: Inhibiting FAK signaling activates the Wnt pathway and vice versa. As the identification of effective Wnt inhibitors to translate in the clinical setting remains an outstanding challenge, further understanding of the functional interaction between Wnt and FAK could reveal new therapeutic opportunities and approaches greatly needed in clinical oncology. In this review, we summarize some of the most relevant interactions between FAK and Wnt in different cancers, address the current landscape of Wnt- and FAK-targeted therapies in different clinical trials, and discuss the rationale for targeting the FAK–Wnt crosstalk, along with the possible translational implications.
Keywords	FAK ; Wnt ; cell signaling ; cancer ; malignant mesothelioma ; clinical trials ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Membrane-Interacting DNA Nanotubes Induce Cancer Cell Death

Samet Kocabey / Aslihan Ekim Kocabey / Roger Schneiter / Curzio Rüegg

Nanomaterials, Vol 11, Iss 2003, p

2021 Volume 2003

Abstract: DNA nanotechnology offers to build nanoscale structures with defined chemistries to precisely position biomolecules or drugs for selective cell targeting and drug delivery. Owing to the negatively charged nature of DNA, for delivery purposes, DNA is ... ...

Abstract	DNA nanotechnology offers to build nanoscale structures with defined chemistries to precisely position biomolecules or drugs for selective cell targeting and drug delivery. Owing to the negatively charged nature of DNA, for delivery purposes, DNA is frequently conjugated with hydrophobic moieties, positively charged polymers/peptides and cell surface receptor-recognizing molecules or antibodies. Here, we designed and assembled cholesterol-modified DNA nanotubes to interact with cancer cells and conjugated them with cytochrome c to induce cancer cell apoptosis. By flow cytometry and confocal microscopy, we observed that DNA nanotubes efficiently bound to the plasma membrane as a function of the number of conjugated cholesterol moieties. The complex was taken up by the cells and localized to the endosomal compartment. Cholesterol-modified DNA nanotubes, but not unmodified ones, increased membrane permeability, caspase activation and cell death. Irreversible inhibition of caspase activity with a caspase inhibitor, however, only partially prevented cell death. Cytochrome c-conjugated DNA nanotubes were also efficiently taken up but did not increase the rate of cell death. These results demonstrate that cholesterol-modified DNA nanotubes induce cancer cell death associated with increased cell membrane permeability and are only partially dependent on caspase activity, consistent with a combined form of apoptotic and necrotic cell death. DNA nanotubes may be further developed as primary cytotoxic agents, or drug delivery vehicles, through cholesterol-mediated cellular membrane interactions and uptake.
Keywords	DNA nanotechnology ; DNA nanostructure ; targeted delivery ; cytochrome c ; cholesterol ; cytotoxicity ; Chemistry ; QD1-999
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Breast Cancer Stem Cells with Tumor- versus Metastasis-Initiating Capacities Are Modulated by TGFBR1 Inhibition

Flavia Fico / Mélanie Bousquenaud / Curzio Rüegg / Albert Santamaria-Martínez

Stem Cell Reports, Vol 13, Iss 1, Pp 1-

2019 Volume 9

Abstract: Summary: Cancer stem cells (CSCs) are defined by their ability to regenerate a tumor upon transplantation. However, it is not yet clear whether tumors contain a single CSC population or different subsets of cells with mixed capacities for initiating ... ...

Abstract	Summary: Cancer stem cells (CSCs) are defined by their ability to regenerate a tumor upon transplantation. However, it is not yet clear whether tumors contain a single CSC population or different subsets of cells with mixed capacities for initiating primary and secondary tumors. Using two different identification strategies, we studied the overlap between metastatic stem cells and tumor-initiating cells (TICs) in the MMTV-PyMT model. Our results show that in the MMTV-PyMT model, Lin−CD90−ALDHhigh cells retained a high tumor-initiating potential (TIP) in orthotopic transplants, in contrast to Lin−CD24+CD90+, which retained higher metastatic capacity. Interestingly, suppression of TGFβ signaling increased TIC numbers. We here describe the existence of distinct populations of CSCs with differing capacities to initiate tumors in the primary or the secondary site. Inhibiting TGFβ signaling shifts the balance toward the former, which may have unanticipated implications for the therapeutic use of TGFβ/TGFBR1 inhibitors. : In this study, Santamaria-Martínez and colleagues isolated cancer stem cells from MMTV-PyMT mammary gland tumors based on the expression of either CD24 and CD90 or on ALDH activity and showed that metastasis- and tumor-initiating features are not necessarily shared by the same cell type. Additionally, they found that TGFBR1 inhibition prevents metastasis but promotes the expansion of tumor-initiating cells. Keywords: cancer stem cells, TGFBR1, breast cancer, metastasis
Keywords	Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Targeting of the NOX1/ADAM17 Enzymatic Complex Regulates Soluble MCAM-Dependent Pro-Tumorigenic Activity in Colorectal Cancer

Jimmy Stalin / Oriana Coquoz / Rachel Jeitziner Marcone / Stephane Jemelin / Nina Desboeufs / Mauro Delorenzi / Marcel Blot-Chabaud / Beat A. Imhof / Curzio Ruegg

Biomedicines, Vol 11, Iss 12, p

2023 Volume 3185

Abstract: The melanoma cell adhesion molecule, shed from endothelial and cancer cells, is a soluble growth factor that induces tumor angiogenesis and growth. However, the molecular mechanism accounting for its generation in a tumor context is still unclear. To ... ...

Abstract	The melanoma cell adhesion molecule, shed from endothelial and cancer cells, is a soluble growth factor that induces tumor angiogenesis and growth. However, the molecular mechanism accounting for its generation in a tumor context is still unclear. To investigate this mechanism, we performed in vitro experiments with endothelial/cancer cells, gene expression analyses on datasets from human colorectal tumor samples, and applied pharmacological methods in vitro/in vivo with mouse and human colorectal cancer cells. We found that soluble MCAM generation is governed by ADAM17 proteolytic activity and NOX1-regulating ADAM17 expression. The treatment of colorectal tumor-bearing mice with pharmacologic NOX1 inhibitors or tumor growth in NOX1-deficient mice reduced the blood concentration of soluble MCAM and abrogated the anti-tumor effects of anti-soluble MCAM antibodies while ADAM17 pharmacologic inhibitors reduced tumor growth and angiogenesis in vivo. Especially, the expression of MCAM, NOX1, and ADAM17 was more prominent in the angiogenic, colorectal cancer-consensus molecular subtype 4 where high MCAM expression correlated with angiogenic and lymphangiogenic markers. Finally, we demonstrated that soluble MCAM also acts as a lymphangiogenic factor in vitro. These results identify a role for NOX1/ADAM17 in soluble MCAM generation, with potential clinical therapeutic relevance to the aggressive, angiogenic CMS4 colorectal cancer subtype.
Keywords	NADPH oxidases ; melanoma cell adhesion molecule ; angiogenesis ; lymphangiogenesis ; pharmacologic inhibitors ; colorectal tumor ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Emodin Inhibits Inflammation, Carcinogenesis, and Cancer Progression in the AOM/DSS Model of Colitis-Associated Intestinal Tumorigenesis

Yunsha Zhang / Weiling Pu / Mélanie Bousquenaud / Sarah Cattin / Jelena Zaric / Li-kang Sun / Curzio Rüegg

Frontiers in Oncology, Vol

2021 Volume 10

Abstract: Colorectal cancer (CRC) is one of the most common cancer worldwide. Chronic inflammation contributes to CRC development and progression. Emodin, is a natural anthraquinone derivative with anti-oxidant, anti-inflammatory, and anti-tumor activities. We ... ...

Abstract	Colorectal cancer (CRC) is one of the most common cancer worldwide. Chronic inflammation contributes to CRC development and progression. Emodin, is a natural anthraquinone derivative with anti-oxidant, anti-inflammatory, and anti-tumor activities. We used the AOM/DSS model of colitis-associated intestinal tumorigenesis to characterize the effect of Emodin on inflammation and tumorigenesis at weeks 3, 5, and 14 after initiation with AOM. At all three time points, Emodin (50 mg/kg) reduced inflammatory cell (i.e. CD11b+ and F4/80+) recruitment, cytokine (i.e. TNFα, IL1α/β, IL6, CCL2, CXCL5) and pro-inflammatory enzymes (i.e. COX-2, NOS2) expression in the tumor microenvironment, while promoting recruitment of CD3+ T lymphocytes at 14 weeks. Emodin decreased the incidence of premalignant lesions (adenoma) at week 3, the incidence of dysplastic lesions and carcinomas at week 5, and the incidence, size and the invasiveness of carcinomas at week 14. Emodin also reduced the acute clinical intestinal symptoms (i.e. bleeding and diarrhea) during DSS treatment. In vitro, Emodin inhibited the expression of pro-inflammatory mediators by LPS-stimulated RAW 264.7 macrophages, and reduced viability, adhesion, migration, and fibroblasts-induced invasion of SW620 and HCT116 colon cancer cells. In conclusion, this work demonstrates that Emodin suppresses carcinogenesis-associated intestinal inflammation and prevents AOM/DSS-induced intestinal tumorigenesis and progression. These results instigate further studies on Emodin as a natural agent for the prevention or treatment of colorectal cancer.
Keywords	emodin ; colorectal cancer ; Chinese medicine ; tumor microenvironment ; inflammation ; T lymphocytes ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress

Kedar Ghimire / Jelena Zaric / Begoña Alday-Parejo / Jochen Seebach / Mélanie Bousquenaud / Jimmy Stalin / Grégory Bieler / Hans-Joachim Schnittler / Curzio Rüegg

Cells, Vol 8, Iss 5, p

2019 Volume 388

Abstract: Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca 2+ /calmodulin-dependent ... ...

Abstract	Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca 2+ /calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an adaptor protein that stabilizes epithelial and endothelial cell-cell contacts. The aim of this study was to assess the unknown role of endothelial cell MAGI1 in response to fluid shear stress. We show constitutive expression and co-localization of MAGI1 with vascular endothelial cadherin (VE-cadherin) in endothelial cells at cellular junctions under static and laminar flow conditions. Fluid shear stress increases MAGI1 expression. MAGI1 silencing perturbed flow-dependent responses, specifically, Krüppel-like factor 4 (KLF4) expression, endothelial cell alignment, eNOS phosphorylation and NO production. MAGI1 overexpression had opposite effects and induced phosphorylation of PKA, AMPK, and CAMKII. Pharmacological inhibition of PKA and AMPK prevented MAGI1-mediated eNOS phosphorylation. Consistently, MAGI1 silencing and PKA inhibition suppressed the flow-induced NO production. Endothelial cell-specific transgenic expression of MAGI1 induced PKA and eNOS phosphorylation in vivo and increased NO production ex vivo in isolated endothelial cells. In conclusion, we have identified endothelial cell MAGI1 as a previously unrecognized mediator of fluid shear stress-induced and PKA/AMPK dependent eNOS activation and NO production.
Keywords	fluid shear stress ; MAGI1 ; signal transduction ; eNOS ; endothelial cell ; nitric oxide/NO ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Not just Fundamental Research

Scott Capper / Eliav Haskal / Andreas Kilbinger / Lucas Montero de Espinosa / Barbara Rothen-Rutishauser / Curzio Rüegg / Christoph Weder

CHIMIA, Vol 73, Iss 1-

Education, Equal Opportunities, Knowledge and Technology Transfer, and Communication at the NCCR Bio-Inspired Materials

2019 Volume 2

Abstract: Abstract: Besides conducting excellent fundamental research in domains of strategic importance, the National Centers of Competence in Research (NCCRs) also aim to become centers of reference for education, equal opportunities, and knowledge and ... ...

Abstract	Abstract: Besides conducting excellent fundamental research in domains of strategic importance, the National Centers of Competence in Research (NCCRs) also aim to become centers of reference for education, equal opportunities, and knowledge and technology transfer. These activities are supported by a communication strategy focused on specific target groups. This article describes some of the main strategic goals and achievements of the NCCR Bio-Inspired Materials, presents the main activities launched by the Center throughout its first funding phase, and provides a glimpse of new plans and directions for the second phase.
Keywords	Communication ; Education and training ; Equal opportunities ; Knowledge and technology transfer ; Chemistry ; QD1-999
Language	German
Publishing date	2019-02-01T00:00:00Z
Publisher	Swiss Chemical Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Bio-Inspired Amplification Cascade for the Detection of Rare Cancer Cells

Curzio Rüegg / Corine Reis / Sarah Rafiee / Laura Rodriguez-Lorenzo / Jonathan List / Barbara Rothen-Rutishauser / Michael Mayer / Alke Petri-Fink

CHIMIA, Vol 73, Iss 1-

2019 Volume 2

Abstract: Abstract: The main cause of cancer-related death is due to cancer cell spreading and formation of secondary tumors in distant organs, the so-called metastases. Metastatic cancer cells are detectable in the blood of cancer patients as circulating tumor ... ...

Abstract	Abstract: The main cause of cancer-related death is due to cancer cell spreading and formation of secondary tumors in distant organs, the so-called metastases. Metastatic cancer cells are detectable in the blood of cancer patients as circulating tumor cells (CTC) and may be exploited for prognostic and monitoring purposes, including in breast cancer. Due to their very low frequency, however, their quantitative detection remains a challenge in clinical practice. Nature has developed mechanisms to amplify rare biological events or weak signals, such as intracellular signaling pathways, cytokine networks or the coagulation cascades. At the National Center for Competence in Research (NCCR) in Bio-Inspired Materials we are coupling gold nanoparticle-based strategies with fibrinogen and DNA bio-inspired amplification cascades to develop an in vitro test to specifically and sensitively detect CTCs in patients' blood. In this article, we describe the biological context, the concept of bio-inspired amplification, and the approaches chosen. We also discuss limitations, open questions and further potential biomedical applications of such an approach.
Keywords	Amplification ; Breast cancer ; Fibrin ; Hybridization ; In vitro diagnostic ; Nanoparticle ; Chemistry ; QD1-999
Subject code	610
Language	German
Publishing date	2019-02-01T00:00:00Z
Publisher	Swiss Chemical Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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