Transcriptional regulation of tumor-induced angiogenesis

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The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways. This work, pioneered by Stephin Vervoort, Olivier de Jong, Cindy Frederiks and Guy Roukens is a collaboration between many groups within The Netherlands and the United Kingdom and is published in eLife here.

Regulation of oligodendrocyte differentiation by SOX4

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SOX4 has been shown to promote neuronal differentiation both in the adult and embryonic neural progenitors. Ectopic SOX4 expression has also been shown to inhibit oligodendrocyte differentiation in mice, however the underlying molecular mechanisms remain poorly understood. Here we demonstrate that SOX4 regulates transcriptional targets associated with neural development in neural stem cells (NSCs), reducing the expression of genes promoting oligodendrocyte differentiation. SOX4 levels decreased during oligodendrocyte differentiation in vitro while SOX4 knockdown induces increased oligodendrocyte differentiation. Conversely, conditional SOX4 overexpression decreases the percentage of maturing oligodendrocytes, suggesting that SOX4 inhibits maturation from precursor to mature oligodendrocyte. We identify the transcription factor Hes5 as a direct SOX4 target gene and we show that conditional overexpression of Hes5 rescues the increased oligodendrocyte differentiation mediated by SOX4 depletion in NSCs. Taken together, these observations support a novel role for SOX4 in NSC by controlling oligodendrocyte differentiation through induction of Hes5 expression. This work was performed by Luca Braccioli as part of his thesis project in the Coffer Lab and has been published in Stem Cell Reports.


The role of WNT signaling in mature T cells: TCF Is coming home

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T cell factor, the effector transcription factor of the WNT signaling pathway, was so named because of the primary observation that it is indispensable for T cell development in the thymus. Since this discovery, the role of this signaling pathway has been extensively studied in T cell development, hematopoiesis, and stem cells; however, its functional role in mature T cells has remained relatively underinvestigated. Over the last few years, various studies have demonstrated that T cell factor can directly influence T cell function and the differentiation of Th1, Th2, Th17, regulatory T cell, follicular helper CD4+ T cell subsets, and CD8+ memory T cells. In a recent review paper in Journal of Immunology with Jorg van Loosdregt, we discuss the molecular mechanisms underlying these observations and place them in the general context of immune responses. Furthermore, we explore the implications and limitations of these findings for WNT manipulation as a therapeutic approach for treating immune-related diseases. You can find out more here.

Forkhead box transcription factors as context-dependent regulators of lymphocyte homeostasis

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Lymphocytes have evolved to react rapidly and robustly to changes in their local environment by using transient adaptations and by regulating their terminal differentiation programmes. Forkhead box transcription factors (FTFs) can direct leukocyte-specific responses, and their functional diversification promotes a high degree of context-dependent specification. Many, often antagonistic, FTFs have overlapping expression patterns and can thereby compete for binding to the same chromosomal target sequences. Multiple molecular mechanisms also connect extracellular signals to the expression and functionality of specific FTFs and, in this way, fine-tune their activity. Through these diverse mechanisms, FTFs can function as context-dependent rheostats responding to diverse environmental stimuli. Focusing on the various mechanisms by which their functional activity is modulated, as well as on their mechanisms of action, we discuss how specific FTFs control lymphocyte function, allowing for the establishment and maintenance of immune homeostasis. This review, written together with Dietmar Zaiss (University of Edinburgh) has been published in Nature Immunology Reviews

STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells

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T-cell acute lymphoblastic leukemia (T-ALL) constitutes an aggressive subset of ALL, the most frequent childhood malignancy. Whereas interleukin-7 (IL-7) is essential for normal T-cell development, it can also accelerate T-ALL development in vivo and leukemia cell survival and proliferation by activating phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling. Here, we investigated whether STAT5 could also mediate IL-7 T-ALL-promoting effects. We show that IL-7 induces STAT pathway activation in T-ALL cells and that STAT5 inactivation prevents IL-7–mediated T-ALL cell viability, growth, and proliferation. At the molecular level, STAT5 is required for IL-7-induced downregulation of p27kip1and upregulation of the transferrin receptor, CD71. Surprisingly, STAT5 inhibition does not significantly affect IL-7–mediated Bcl-2 upregulation, suggesting that, contrary to normal T-cells, STAT5 promotes leukemia cell survival through a Bcl-2-independent mechanism. STAT5 chromatin immunoprecipitation sequencing and RNA sequencing reveal a diverse IL-7-driven STAT5-dependent transcriptional program in T-ALL cells, which includes BCL6 inactivation by alternative transcription and upregulation of the oncogenic serine/threonine kinase PIM1. Pharmacological inhibition of PIM1 abrogates IL-7–mediated proliferation on T-ALL cells, indicating that strategies involving the use of PIM kinase small-molecule inhibitors may have therapeutic potential against a majority of leukemias that rely on IL-7 receptor (IL-7R) signaling. Overall, our results demonstrate that STAT5, in part by upregulating PIM1 activity, plays a major role in mediating the leukemia-promoting effects of IL-7/IL-7R. 

This work was a collaboration with the Barata Lab (IMM, Lisbon) and has been published in Blood Advances

Turning an tumor suppressor into an oncogene

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SOX4 is an important component in the tumor-promoting transcriptional response induced by TGF-beta in breast cancer. Here, Stephin Vervoort and Ana Rita Lourenco performed an unbiased transcription factor interaction screen and identified SMAD3 as a novel interaction partner of SOX4. SOX4 was found to specifically control a pro-oncogenic subset of SOX4/SMAD3 co-bound TGFbeta-target genes, associated with poor-disease outcome. Our findings thus highlight a novel role of SOX4 in the TGFbeta-pathway by cooperatively regulating target genes with SMAD3 in a context-dependent manner, thereby skewing TGFbeta-responses. This work has been published in Nucleic Acid Research

Regenerative Medicine Utrecht looking for 29 new international PhD students

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With an aging population and rising healthcare costs, the need for organs, tissues and personalized strategies in medicine has never been greater. Recent developments in medical technologies such as 3D-bioprinting, stem cell therapy and gene editing hold the promise to provide tissues for transplantation, tailor-made medical solutions and opportunities to help the body repair and regenerate itself. However, our understanding of the fundamentals of cell, tissue and organ regeneration and their potential application for therapeutic purposes are still in its infancy. For Regenerative Medicine to fully capture its potential, a synergistic and multidisciplinary effort remains necessary to achieve essential scientific breakthroughs.

Together the University Medical Center Utrecht (coordinator) and the Utrecht University offer a unique international PhD programme, named RESCUE, for excellent PhD candidates (early stage researchers, ESRs) with 29 high level fellowships for a joint doctorate programme within the Regenerative Medicine Centre Utrecht. The RESCUE programme aims to enhance the potential and future career perspectives of researchers by providing a global training network including over 50 excellent academic and industrial partner organisations, creating a new generation of research experts, empowering them to take leading positions in the field of Regenerative Medicine world-wide.

PhD positions are for Master's students who have not worked in The Netherlands for more than 12 months in the last 3 years. Positions are available in the fields of: stem cells & organoids, cardiovascular regeneration and musculoskeletal regeneration. The Coffer Lab also has a joint position available. 

More information and the application procedure can be found here www.rescue-cofund.eu.