Ovarian cancer is the most lethal malignancy in the United States. While studies on ovarian cancer pathogenesis were mainly focused on the epithelial component of the tumor, understanding in the role of cancer associated fibroblasts (CAFs) in ovarian cancer progression is limited. In the present study, we describe the use of microdissected transcriptome profiles for the identification of cancerstroma crosstalk networks with prognostic value, which presents a unique opportunity for developing new treatment strategies for ovarian cancer.
Systematic Identification of Druggable Epithelial-Stromal Crosstalk Signaling Networks in Ovarian Cancer.
Specimen part
View SamplesBased on RNA-seq, we performed transcriptomic profiling to examine the similarities or differences between BICA (bone-in-culture array) and IVBL (in vivo bone lesion). CIBERSORT analysis reveals that the major local cellular components are comparable between BICA and IVBL, but differ dramatically in orthotopic tumors. Principle component analysis of human RNAs indicated that the transcriptomic profiles of cancer cells in BICA are more closely mimicking IVBL, as compared to cancer cells in 2D and in orthotopic tumors. These results provide transcriptome-wide evidence supporting BICA as a platform to mimic bone microenvironment. Overall design: 2D culture cells, orthotopic tumors, BICA samples and bone lesions, all developed by MCF-7, are subject to NGS and then analyzed.
Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies.
Specimen part, Cell line, Subject
View SamplesBased on RNA-seq, we performed transcriptomic profiling to examine the differences between Orthotopic and IVBL (in vivo bone lesion). We found Calcium signalling is upregulated in IVBL and correlated to the expression of gap junctions. Overall design: Orthotopic tumors and Bone lesions, all developed by MCF-7, are subject to NGS and then analyzed.
The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability.
Specimen part, Subject
View SamplesBased on next generation RNA-seq, we examed Arsenic trioxide treatment (ATO) effect on MSCs-interacting MCF7 cells in 3D cultures. We found gap junction protein Cx43 is dramatically downregulated after ATO treatment.. Overall design: human breast cancer cell line MCF-7 cells cocultured with mouse MSCs in 3D culture, with or without ATO treatment, are subject to NGS and then analyzed.
The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability.
Specimen part, Cell line, Treatment, Subject
View SamplesRNA-seq data of Group 3 and 4 medulloblastoma with digoxin treatment. Overall design: Investigate the differential expressed genes in Group 3 and 4 Medulloblastoma under digoxin treatment
Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma.
Specimen part, Disease, Disease stage, Treatment, Subject
View SamplesThe new official nomenclature subdivides human monocytes into three subsets, classical (CD14++CD16-), intermediate (CD14++CD16+) and nonclassical (CD14+CD16+). Here, we comprehensively define relationships and unique characteristics of the three human monocyte subsets using microarray and flow cytometry analysis. Our analysis revealed that the intermediate and nonclassical monocyte subsets were most closely related. For the intermediate subset, majority of genes and surface markers were expressed at an intermediary level between the classical and nonclassical subset. There features therefore indicate a close and direct lineage relationship between the intermediate and nonclassical subset. From gene expression profiles, we define unique characteristics for each monocyte subset. Classical monocytes were functionally versatile, due to the expression of a wide range of sensing receptors and several members of the AP-1 transcription factor family. The intermediate subset was distinguished by high expression of MHC class II associated genes. The nonclassical subset were most highly differentiated and defined by genes involved in cytoskeleton rearrangement that explains their highly motile patrolling behavior in vivo. Additionally, we identify unique surface markers, CLEC4D, IL-13RA1 for classical, GFRA2, CLEC10A for intermediate and GPR44 for nonclassical. Our study hence defines the fundamental features of monocyte subsets necessary for future research on monocyte heterogeneity.
Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets.
Specimen part, Subject
View SamplesGene Expression Profiling of Breast Cancer Patients with Brain Metastases Brain metastases confer the worst prognosis of breast cancer as no therapy exists that prevents or eliminates the cancer from spreading to the brain. We developed a new computational modeling method to derive specific downstream signaling pathways that reveal unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available gene expression data of patients. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed the specific CSBs for each metastasis that satisfy that (1) CSB proteins are activated by the maximal number of enriched signaling pathways specific to this metastasis, and (2) CSB proteins involve in the most differential expressed coding-genes specific to the specific breast cancer metastasis. The identified signaling networks for the three types of metastases contain 31, 15, and 18 proteins, respectively, and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases of breast cancer. We performed in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Two known drugs, Sunitinib (FDA approved for renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor) and Dasatinib (FDA approved for chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia), were shown to prohibit the metastatic colonization in brain.
Novel modeling of cancer cell signaling pathways enables systematic drug repositioning for distinct breast cancer metastases.
Time
View SamplesBrain development requires a massive increase in brain lipogenesis and accretion of the essential omega-3 fatty acid docosahexaenoic acid (DHA). Brain acquisition of DHA is primarily mediated by the transporter Major Facilitator Superfamily Domain containing 2a (Mfsd2a) expressed in the endothelium of the blood-brain barrier. Mfsd2a transports DHA and other polyunsaturated fatty acids esterified to lysophosphatidylcholine (LPC-DHA). However, the function of Mfsd2a and DHA in brain development is incompletely understood. Using vascular endothelial-specific (2aECKO) and inducible vascular endothelial-specific (2aiECKO) deletion of Mfsd2a in mice, we found Mfsd2a to be uniquely required postnatally at the blood-brain barrier for normal brain growth and DHA accretion, with DHA deficiency preceding the onset of microcephaly. Gene expression profiling analysis of these DHA deficient brains indicated that Srebp-1 and Srebp-2 pathways were highly elevated.
The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain.
Specimen part
View SamplesGene regulation at the maternal-embryonic transition in the pre-implantation mouse embryo is not well understood. We knock down Ccna2 to establish proof-of-concept that antisense morpholino oligonucleotides can be used to target specific genes. We applied this strategy to study Oct4 and discovered that Oct4 is required prior to blastocyst development. Specifically, gene expression is altered as early as the 2-cell stage in Oct4-knockdown embryos.
A novel and critical role for Oct4 as a regulator of the maternal-embryonic transition.
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Orchestrated intron retention regulates normal granulocyte differentiation.
Specimen part
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