62 research outputs found
Evolutionary Divergence in the Hedgehog Pathway
No full textI like this paper because the findings that it reports took me completely by surprise—and serve as a constant reminder of the fallibility of my own scientific logic! A few years earlier, Rune Toftgård had invited me to give a talk at the Karolinska Institute about our analysis of the Hedgehog (HH) signaling pathway in Drosophila. During the course of my visit, Rune told me that he and his colleagues were planning to make a mouse knockout mutation of the Suppressor of fused (SUFU) gene, an exercise that I opined would be of only marginal value, given the dispensable nature of the orthologous gene in Drosophila. Indeed, my skepticism seemed well placed when we subsequently found that morpholino-mediated knockdown of SUFU has a rather subtle effect on HH signaling in zebrafish. But clearly undeterred by my advice, Toftgård and colleagues proceeded to generate a SUFU null mutation, the phenotype of which demonstrates its pivotal role in mammalian HH signaling!This PaperPick refers to “Genetic Elimination of Suppressor of Fused Reveals an Essential Repressor Function in the Mammalian Hedgehog Signaling Pathway,” by J. Svärd, K. Heby-Henricson, M. Persson-Lek, B. Rozell, M. Lauth, A. Bergström, J. Ericson, R. Toftgård, and S. Teglund, published in February 2006.Video AbstractDrs. Toftgård, Teglund, and Heby-Henricson offer a personal account of the work published in this paper and highlight areas of current research on the mechanisms of Hedgehog signal transduction
Smoothing Out Drug Resistance
No full textSmoothened inhibitors have emerged as successful treatment alternatives for Hedgehog pathway-dependent tumors, but they are linked with the appearance of drug resistance. In this issue of Cancer Cell, Kim and colleagues overcome such resistance by combining approved drugs itraconazole and arsenic trioxide, thus opening a path toward new treatment options
Non-Canonical Activation of GLI Transcription Factors: Implications for Targeted Anti-Cancer Therapy
No full textTumour suppressors in liver carcinogenesis.
No full textThe circuitous cell signalling pathways of hepatocytes comprise several factors that operate to downgrade or even interrupt the transmission of a given signal. These down-regulating influences are essential to keep cell proliferation and cell survival in check and if impaired, can alter a delicate balance in favour of cell proliferation. Each signalling pathway that has been implicated in carcinogenesis is influenced by both oncogenic factors that promote tumour growth when activated as well as tumour suppressor proteins that have to be impaired to favour tumour growth. This summary of the Tumour Suppressors in Liver Carcinogenesis Symposium held at the 2007 EASL Annual Meeting discusses four pathways with pre-eminent tumour suppressor activity, each involved in hepatocarcinogenesis: p53, mTOR, beta-catenin and hedgehog
Abstract 1407: A transgenic mouse model for the Hedgehog pathway effector GLI1 induced mammary gland tumors.
No full textAbstract Increased expression of the Hedgehog (Hh) signaling pathway effector GLI1 in breast cancer patients has been shown to correlate inversely with disease free and overall survival. Activation of the Hh signaling pathway is known to promote proliferation of breast cancer cells and stimulate mammosphere formation. In addition, the Hh signaling pathway has been reported activated in CD44 positive breast cancer stem cells. Despite the evidence supporting a role for Hh signaling in breast cancer development and maintenance, the model systems to study the Hh pathway in breast carcinogenesis are limited. We used a transgenic mouse model to show that GLI1 expression in the mammary gland cause tumor formation. The GLI1 induced primary tumors showed different histological characteristics, suggesting that the GLI1 expression influenced the tumor initiating cells. The GLI1 induced primary tumors were orthotopically transplanted on NOD/SCID mice and we have established serial transplantable tumor lines. The different histological characteristics of the individual primary tumors have been maintained for >10 serial transplantations in NOD/SCID mice. The stem cell marker CD44 is expressed in the mouse mammary gland ducts. The CD44 positive cell population is increased in the GLI1 induced tumors. The G protein coupled receptor (GPCR) like protein Lgr5 has been suggested as a stem cell marker in several tissues, including mammary gland. We show that cells in the basal layer of the adult mammary gland ducts express Lgr5. The Lgr5 positive cell population is increased in the GLI1 induced tumors, suggesting a basal like characteristic of these tumors. Taken together, our data show that expression of GLI1 in the mammary gland result in formation of mammary gland tumors with heterogeneous histological characteristics. The cell populations identified by the stem cell markers CD44 or Lgr5 are increased in the GLI1 induced tumors compared with the normal mammary gland. Furthermore, we have established serial transplantable GLI1 induced mammary gland tumor lines. These serial transplantable tumor lines are novel tools to address the role of GLI1 expression in breast carcinogenesis. Citation Format: Jens H. Norum, Agneta Andersson, Maria Kasper, Therese Sørlie, Rune Toftgård. A transgenic mouse model for the Hedgehog pathway effector GLI1 induced mammary gland tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1407. doi:10.1158/1538-7445.AM2013-140
Visualisering av FRAM
No full textThe Functional Resonance Accident Model is a method developed to analyze complex systems for the purpose of accident prevention. In FRAM-analysis a visualization of the complex system is created as an aid for identifying points of interaction in the system where the risk of accidents is high, and to determine where preventive measures are to be placed. FRAM Visualizer is a computer program developed as a tool for creating such visualizations. Many usability problems have been identified in FRAM visualizations created both manually according to established method and by using the FRAM Visualizer software. The purpose of this paper is to give a basis for how FRAM visualizations can be improved in accordance with usability criteria for use in future qualitative studies. The author suggests alterations to the FRAM visualization to resolve usability issues identified in previous articles and to achieve usability goals derived from visual communication theory. The design process is guided by established design principles. The author outlines a proposal for usability testing of the redesigned FRAM visualization to verify that it achieves the usability goals. The author concludes that though the redesign offers solutions for the most important problems (providing the user with detailed information as a basis for analysis and enabling the layout of clearer and more easily overviewed structures in the FRAM diagrams) the visualization must be subjected to usability testing to determine whether the design criteria have been achieved and the solutions of design problems are satisfactory. The redesigned visualization appears most effective when presented in an interactive format. It often requires multiple optimized static views to satisfactorily support browsing both in overview and in detail.
Epidermal stem cells in physiological tissue regeneration, wound healing and cancer
No full textThe mammalian skin is a versatile organ that protects from external harm, regulates the body temperature, and provides the touch sensation. Its epithelium, the epidermis, forms several highly regenerative structures as the hair follicle (HF), the sebaceous gland (SG), and the interfollicular epidermis (IFE). Lineage tracing experiments in mice have demonstrated that several basal cell populations in the IFE and HF have the capacity to renew the epidermis during homeostasis, and also contribute to wound healing and cancer formation. However, clear insights distinguishing the different stem cell populations and defining their exact spatio-temporal patterns of contribution were lacking.Expression of Lgr5 marks stem cells located in the HF bulge and hair germ. We used lineage tracing of Lgr5-expressing (Lgr5+) cells in mice to investigate how wound healing affects the capacity of epidermal stem cells to initiate skin cancer. Induction of basal cell carcinoma (BCC) through activation of Hedgehog signalling in the entire basal layer confirmed that wounding strongly increases the incidence and severity of BCC-like lesions. Targeting the oncogenic mutation to Lgr5+ cells revealed that transformed HF cells are able to leave their natural environment and establish tumours in the IFE in response to wounding. Thus, wounding activates HF stem cells to expand and migrate to unaffected tissue areas, thereby augmenting BCC development.Since it was discovered that Lgr6 is another epidermal stem cell marker, we set out to explore the role of Lgr6+ stem cells during epidermal homeostasis. Detailed analysis of the lineagetracing pattern of the Lgr6+ cells populations in the isthmus, SG, and IFE disclosed that these resident Lgr6+ populations independently maintain their respective compartment. The mode of tissue renewal displayed by all three Lgr6+ cell populations was in accordance with a stochastic division of one type of progenitor cell. These results highlight that stochastic stem cell renewal is relevant in many types of rapidly proliferating epithelia.We further investigated the susceptibility of the different epidermal compartments harbouring Lgr6+ stem cells towards BCC initiation and evaluated the influence of the microenvironment on tumour formation. Knockout of Ptch1 in Lgr6+ cells resulted in highly accelerated BCC development within the HF isthmus and the touch dome niches in the IFE. The touch dome and the isthmus are both associated with cutaneous nerve fibres, and show several morphological and molecular features that are highly similar to BCC. This demonstrates that these two niches promote the response of the epithelial cells to the oncogenic stimulus.In summary, tracking the fate of Lgr5- and Lgr6-expressing epidermal stem cells during homeostasis, wound healing and early cancer formation shed light on the similarities and differences between distinct stem cell populations in the skin. The results illustrate how stem cell renewal is achieved, elucidate the early steps of skin cancer development, and underline the influence of the microenvironment on the behaviour of tissue stem cells.List of scientific papersI. Maria Kasper, Viljar Jaks, Alexandra Are, Åsa Bergström, Anja Schwäger, Jessica Svärd, Stefan Teglund, Nick Barker and Rune Toftgård. Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(10):4099-4104. https://doi.org/10.1073/pnas.1014489108 II. Anja Füllgrabe, Simon Joost, Alexandra Are, Tina Jacob, Unnikrishnan Sivan, Andrea Haegebarth, Sten Linnarsson, Benjamin D. Simons, Hans Clevers, Rune Toftgård and Maria Kasper. Dynamics of Lgr6+ progenitor cells in the hair follicle, sebaceous gland, and interfollicular epidermis. Stem Cell Reports, 2015, 5(5):843-855. https://doi.org/10.1016/j.stemcr.2015.09.013 III. Anja Füllgrabe, Alexandra Are, Rune Toftgård and Maria Kasper. Healthy skin harbors pre-existing micro-niches that promote tumor formation. [Manuscript]</p
UVB-induced association of tumor necrosis factor (TNF) receptor 1/TNF receptor-associated factor-2 mediates activation of Rel proteins
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