1,721,029 research outputs found
The Role of FGF Signaling During Granule Neuron Precursor Development and Tumorigenesis
No full textDevelopment requires a delicate balance of proliferation and differentiation. Too little proliferation can result in dysfunctional tissues, while prolonged or heightened proliferation can result in tumor formation. This is clearly seen with the granule neuron precursors (GNPs) of the cerebellum. Too little proliferation of these cells during development results in ataxia, whereas too much proliferation results in the cerebellar tumor medulloblastoma. While these cells are known to proliferate in response to Shh, it is not clear what controls the differentiation of these cells in vivo. Previous work from our lab has identified basic fibroblast growth factor (bFGF) as a candidate differentiation factor for these cells. In this thesis, I characterize some of the cellular and molecular mechanisms involved in FGF-mediated inhibition (FMI) of Shh-induced GNP proliferation. In addition, I employ FGFR knockouts and a bFGF gain-of-function mouse to determine whether FGF signaling is necessary and/or sufficient for differentiation of GNPs during cerebellar development. Finally, the question of whether bFGF can be effective as a therapeutic agent for in vivo tumor treatment is tested in a transplant model. These experiments indicate that FGF signaling is neither necessary nor sufficient for GNP differentiation during cerebellar development. However, transplanted tumors are potently inhibited by bFGF treatment. Furthermore, FMI is shown to occur around the level of Gli2 processing in the Shh pathway, implying that such a treatment has promise to be widely effective in treatment of Shh-dependent medulloblastomas.</p
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The Role of Gfi1 Family Oncogenes in Medulloblastoma
Full text linkMedulloblastoma (MB) is the most common malignant brain tumor in children. Recent studies have divided MB into four molecular subgroups: WNT, SHH, Group 3, and Group 4. While WNT and SHH tumors have relatively favorable prognoses, Group 3 tumors (characterized by amplification or overexpression of the MYC oncogene) are frequently fatal. The first mouse models of Group 3 MB combine Myc overexpression and p53 loss of function, but they do not precisely recapitulate the disease genetics, as human Group 3 tumors rarely exhibit mutation or loss of p53. Thus, the goal of my research has been to identify secondary hits that can cooperate with MYC and are relevant to human MB.Collaborating with a MB genomics group, we utilized whole genome sequencing (WGS) data and identified two chromosomal loci that are hotspots for rearrangement in Group 3 MB. Using histone chromatin immunoprecipitation sequencing (ChIP-seq) and expression profiling, we found that rearrangements at these loci activate the zinc-finger transcriptional repressors GFI1 and GFI1B by repositioning them adjacent to super-enhancers. Importantly, we demonstrated their functional relevance in an orthotopic transplantation model, where overexpression of either Gfi1 or Gfi1b cooperated strongly with Myc to drive MB formation in mice. These studies highlight a new mechanism for oncogene activation in MB and reveal GFI1/1B as highly prevalent drivers of Group 3 MB. Although the oncogenic potentials of GFI1/1B have previously been studied in blood malignancies, their roles in MB are not well understood. We proceeded to identify the chromatin modifier Lysine demethylase 1 (Lsd1) as a key mediator of Gfi1 function in MB, and integration of ChIP-seq and gene expression data revealed a number of putative target genes and signaling pathways that may be co-regulated by Gfi1/1b and Lsd1. Given the critical interaction between Gfi1 and Lsd1 in these tumors, we tested several small molecule inhibitors of Lsd1 and found that they specifically reduced Gfi1-driven tumor cell growth both in vitro and in vivo. Together these studies confirm the importance of Lsd1 in Gfi1-driven MB and suggest that targeting Lsd1 pharmacologically may be a promising therapeutic strategy
Investigating the Fate of Pre-neoplastic Cells in a Mouse Model of Medulloblastoma
No full textStudying the early stages of cancer can provide important insight into the molecular basis of the disease. In many human cancers, such as prostate, pancreatic, and colon cancer, a pre-neoplastic, or intermediate, stage of the disease has been identified. The pre-neoplastic stage is presumed to be a transition during which normal cells undergo malignant transformation. However, the link between the pre-neoplastic cells and end-stage disease has never been formally established. To investigate the fate of such cells, the patched (ptc) mutant mouse, a model for the brain tumor medulloblastoma was used. Pre-neoplastic cells (PNCs) are found in most ptc mutants during early adulthood, but only 15% of these animals develop tumors. Although PNCs are found in mice that develop tumors, the ability of PNCs to give rise to tumors has never been demonstrated directly, and the fate of cells that do not form tumors remains unknown. Genetic fate mapping and orthotopic transplantation provided definitive evidence that PNCs give rise to tumors and showed that the predominant fate of PNCs that do not form tumors is differentiation. Moreover, N-myc, a gene commonly amplified in medulloblastoma, can dramatically alter the fate of PNCs, preventing differentiation and driving progression to tumors. Importantly, N-myc allows PNCs to grow independently of hedgehog signaling, making the resulting tumors resistant to hedgehog antagonists. These studies provide the first direct evidence that PNCs can give rise to tumors, and demonstrate that identification of genetic changes that promote tumor progression is critical for designing effective therapies for cancer.</p
Hit 'Em Where They Live: Targeting the Cancer Stem Cell Niche
No full textCancer stem cells (CSCs) are thought to be critical for initiation and propagation of many types of cancer. Because these cells are resistant to conventional therapies, they have been very difficult to eliminate. A study in this issue of Cancer Cell suggests that brain tumor CSCs live in a “vascular niche” that promotes their long-term growth and self-renewal. Disrupting this niche impairs CSC self-renewal and thereby significantly inhibits the growth of tumors. Targeting the unique microenvironment of CSCs may be the key to effective cancer therapy
Control of Neuronal Precursor Proliferation in the Cerebellum by Sonic Hedgehog
No full textAbstractCerebellar granule cells are the most abundant type of neuron in the brain, but the molecular mechanisms that control their generation are incompletely understood. We show that Sonic hedgehog (Shh), which is made by Purkinje cells, regulates the division of granule cell precursors (GCPs). Treatment of GCPs with Shh prevents differentiation and induces a potent, long-lasting proliferative response. This response can be inhibited by basic fibroblast growth factor or by activation of protein kinase A. Blocking Shh function in vivo dramatically reduces GCP proliferation. These findings provide insight into the mechanisms of normal growth and tumorigenesis in the cerebellum
Retinal development: Communication helps you see the light
No full textAbstractRecent studies suggest that interactions between neurons, glial cells and endothelial cells are critical in determining the structure of the retina and the optic nerve. Dysregulation of these interactions can lead to disruption of retinal architecture and impairment of vision
Getting at the Root and Stem of Brain Tumors
No full textAbstractBrain tumors are among the most aggressive and intractable types of cancer. Recent studies indicate that brain tumor cells resemble neural stem cells in terms of phenotype, signaling, and behavior in vitro. In light of these similarities, it has been suggested that brain tumors arise from stem cells, that they co-opt stem cell strategies for self-renewal, and even that they contain “cancer stem cells” that are critical for tumor maintenance. We will examine these possibilities and discuss their implications for the understanding and treatment of brain tumors
Spheres without Influence: Dissociating In Vitro Self-Renewal from Tumorigenic Potential in Glioma
No full textThe capacity for self-renewal is thought to be a critical property of tumor-initiating cells. This capacity is often associated with the ability to generate spheres in vitro. In this issue of Cancer Cell, Barrett et al. show that cells lacking sphere-forming ability can still be very efficient at propagating tumors
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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