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Contains fulltext : 247192.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, Progression of epithelial cancers predominantly proceeds by collective invasion of cell groups with coordinated cell-cell junctions and multicellular cytoskeletal activity. Collectively invading breast cancer cells express the gap junction protein connexin-43 (Cx43), yet whether Cx43 regulates collective invasion remains unclear. We here show that Cx43 mediates gap-junctional coupling between collectively invading breast cancer cells and, via hemichannels, adenosine nucleotide/nucleoside release into the extracellular space. Using molecular interference and rescue strategies, we identify that Cx43 hemichannel function, but not intercellular communication, induces leader cell activity and collective migration through the engagement of the adenosine receptor 1 (ADORA1) and AKT signaling. Accordingly, pharmacological inhibition of ADORA1 or AKT signaling caused leader cell collapse and halted collective invasion. ADORA1 inhibition further reduced local invasion of orthotopic mammary tumors in vivo, and joint up-regulation of Cx43 and ADORA1 in breast cancer patients correlated with decreased relapse-free survival. This identifies autocrine purinergic signaling, through Cx43 hemichannels, as a critical pathway in leader cell function and collective invasion.

Contains fulltext : 225785.pdf (Publisher’s version ) (Closed access), Plasticity of cancer invasion and metastasis depends on the ability of cancer cells to switch between collective and single-cell dissemination, controlled by cadherin-mediated cell-cell junctions. In clinical samples, E-cadherin-expressing and -deficient tumours both invade collectively and metastasize equally, implicating additional mechanisms controlling cell-cell cooperation and individualization. Here, using spatially defined organotypic culture, intravital microscopy of mammary tumours in mice and in silico modelling, we identify cell density regulation by three-dimensional tissue boundaries to physically control collective movement irrespective of the composition and stability of cell-cell junctions. Deregulation of adherens junctions by downregulation of E-cadherin and p120-catenin resulted in a transition from coordinated to uncoordinated collective movement along extracellular boundaries, whereas single-cell escape depended on locally free tissue space. These results indicate that cadherins and extracellular matrix confinement cooperate to determine unjamming transitions and stepwise epithelial fluidization towards, ultimately, cell individualization.

Урал рассматривается как особое символическое пространство. Выдвигается гипотеза о том, что этот регион является вернакулярным районом и существует в дискурсе, а его границы могут не совпадать с географическими и/или административными границами. Чтобы их выявить, проводится анализ региональных СМИ, выявляются упоминания принадлежности к Уралу., The author considers the Ural district as a special symbolic space. There is a hypothesis about this area as vernacular region. It exists in the framework of discourse, and its borders may not coincide with geographical and/or administrative boundaries. The authors analyze regional media and reveal references of belonging to the Urals.

Рассматриваются идеологемы современного российского медиадискурса, которые используются для номинации двух полюсов политической сферы — проправительственного и оппозиционного. Анализируется их участие в конструировании конкурирующих моделей идентичности. Вторая часть исследования посвящена оппозиционному полюсу, представленному идеологемами «либерал», «оппозиция» и «пятая колонна»., The authors look at the ideological concepts (ideologems) of the modern Russian media discourse, which are used for nomination of two poles of the political sphere — pro-government and opposition. Thus, these ideologems participate in construction of competing identity models. The second part of the study is devoted to the opposition pole represented by the nominations “liberal”, “opposition” and “the fi fth column”.

This article is dedicated discursive approaches to the definition of identity in regional press. The source of texts is the articles, published in newspaper «Iskra» (Perm kray). We discover verbal signals and meanings, constituting the territorial identity and attitudes to identity., Идентичность рассматривается в русле дискурсивного подхода на основе медиатекстов районной прессы. Эмпирическим материалом послужили тексты отобранные методом сплошной выборки из выпусков газеты «Искра» (Пермский край). Методика исследования включает анализ языковых маркеров региональной идентификации, тематических направлений идентификации и позицию говорящего по отношению к идентификации.

Contains fulltext : 196231.pdf (publisher's version ) (Open Access), Cancer invasion programs are adaptive by switching between metastatic collective and single-cell dissemination; however, current intravital microscopy models for epithelial cancer in mice fail to reliably recreate such invasion plasticity. Using microimplantation of breast cancer spheroids into the murine mammary fat pad and live-cell monitoring, we show microenvironmental conditions and cytoskeletal adaptation during collective to single-cell transition in vivo E-cadherin-expressing 4T1 and E-cadherin-negative MMT tumors both initiated collective invasion along stromal structures, reflecting invasion patterns in 3D organotypic culture and human primary ductal and lobular carcinoma. Collectively invading cells developed weakly oscillatory actin dynamics, yet provided zones for single-cell transitions with accentuated, more chaotic actin fluctuations. This identifies collective invasion in vivo as a dynamic niche and efficient source for single-cell release.

Contains fulltext : 200751.pdf (publisher's version ) (Open Access)

Авторы рассматривают идеологемы современного российского медиадискурса, которые используются для номинации двух полюсов политической сферы — проправительственного и оппозиционного — и тем самым участвуют в конструировании конкурирующих моделей идентичности. Первая часть исследования посвящена проправительственному полюсу, представленному идеологемами «патриот» и «ватник»., The authors look at the ideological concepts (ideologems) of the modern Russian media discourse, which are used for nomination of two poles of the political sphere — pro-government and opposition. Thus, these ideologems participate in construction of competing identity models. The first part of the study is devoted to the pro-government pole represented by the nominations “patriot” and “vatnik”.

Идентичность рассматривается как дискурсивный феномен. Выявляются тематические направления региональной идентификации: географическое, историческое, культурное, личностное. Анализируется позиция говорящего по отношению к идентификации. Констатируется сложный характер региональной идентичности, вступающей во взаимодействие с национально-гражданской идентичностью через дискурсивные практики включения (часть/целое)., The identity is being understood as a discursive phenomenon. The following thematic areas of regional identification are defined: geographical, historical, cultural, and personal. Authors analyse speaker’s position in relation to the identification. It is proved that regional identity interacts with the national and civil identity through discursive practices of inclusion (part / whole).

Radboud University, 28 augustus 2017, Promotor : Friedl, P.H.A. Co-promotor : Wolf, K.A., Contains fulltext : 175290.pdf (publisher's version ) (Open Access)

Contains fulltext : 180410.pdf (publisher's version ) (Open Access)

Contains fulltext : 170562.pdf (publisher's version ) (Closed access), Cancer metastases arise from a multi-step process that requires metastasizing tumor cells to adapt to signaling input from varying tissue environments [1]. As an early metastatic event, cancer cell dissemination occurs through different migration programs, including multicellular, collective, and single-cell mesenchymal or amoeboid migration [2-4]. Migration modes can interconvert based on changes in cell adhesion, cytoskeletal mechanotransduction [5], and/or proteolysis [6], most likely under the control of transcriptional programs such as the epithelial-to-mesenchymal transition (EMT) [7, 8]. However, how plasticity of tumor cell migration and EMT is spatiotemporally controlled and connected upon challenge by the tumor microenvironment remains unclear. Using 3D cultures of collectively invading breast and head and neck cancer spheroids, here we identify hypoxia, a hallmark of solid tumors [9], as an inducer of the collective-to-amoeboid transition (CAT), promoting the dissemination of amoeboid-moving single cells from collective invasion strands. Hypoxia-induced amoeboid detachment was driven by hypoxia-inducible factor 1 (HIF-1), followed the downregulation of E-cadherin, and produced heterogeneous cell subsets whose phenotype and migration were dependent ( approximately 30%) or independent ( approximately 70%) of Twist-mediated EMT. EMT-like and EMT-independent amoeboid cell subsets showed stable amoeboid movement over hours as well as leukocyte-like traits, including rounded morphology, matrix metalloproteinase (MMP)-independent migration, and nuclear deformation. Cancer cells undergoing pharmacological stabilization of HIFs retained their constitutive ability for early metastatic seeding in an experimental model of lung metastasis, indicating that hypoxia-induced CAT enhances cell release rather than early organ colonization. Induced by metabolic challenge, amoeboid movement may thus constitute a common endpoint of both EMT-dependent and EMT-independent cancer