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The acquisition of tamoxifen resistance is a major therapeutic problem in breast cancer. We developed a tamoxifen-resistant MCF-7 (TRM-7) cell line to elucidate the molecular mechanisms and factors associated with acquisition of such resistance. We showed that phosphorylation of STAT3 at tyrosine 705 (Y705) and RANTES expression are increased in response to tamoxifen in human breast cancer cells. On the basis of these results, we hypothesize that upregulated STAT3 phosphorylation and RANTES may be correlated with the development of drug resistance. Here, we showed that STAT3 and RANTES contribute to the maintenance of drug resistance. STAT3 phosphorylation is constitutively retained via a RANTES autocrine loop, which in turn upregulates anti-apoptotic signals in TRM-7 cells. STAT3–RANTES autocrine signaling affected expression of anti-apoptotic BCL-2 family genes and prevented TRM-7 cells from undergoing programmed cell death by inhibiting PARP and caspase-9 cleavage. Subsequently, blockade of STAT3 and RANTES in TRM-7 cells resulted in reduction of anti-apoptotic signals, which was rescued by exogenous RANTES treatment; drug resistance was also restored. Taken together, our results suggested that STAT3–RANTES autocrine signaling is essential for maintenance of drug resistance and inhibition of programmed cell death. These mechanisms of STAT3–RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors. Mol Cancer Res; 11(1); 31–42. ©2012 AACR.

Homologous recombination deficiency (HRD) is a crucial driver of tumorigenesis by inducing impaired repair of double-stranded DNA breaks. Although HRD possibly triggers the production of numerous tumor neoantigens that sufficiently stimulate and activate various tumor-immune responses, a comprehensive understanding of the HRD-associated tumor microenvironment is elusive. To investigate the effect of HRD on the selective enrichment of transcriptomic signatures, 294 cases from The Cancer Genome Atlas-Ovarian Cancer project with both RNA-sequencing and SNP array data are analyzed. Differentially expressed gene analysis and network analysis are performed to identify HRD-specific signatures. Gene-sets associated with mitochondrial activation, including enhanced oxidative phosphorylation (OxPhos), are significantly enriched in the HRD-high group. Furthermore, a wide range of immune cell activation signatures is enriched in HRD-high cases of high-grade serous ovarian cancer (HGSOC). On further cell-type-specific analysis, M1-like macrophage genes are significantly enriched in HRD-high HGSOC cases, whereas M2-macrophage-related genes are not. The immune-response-associated genomic features, including tumor mutation rate, neoantigens, and tumor mutation burdens, correlated with HRD scores. In conclusion, the results of this study highlight the biological properties of HRD, including enhanced energy metabolism, increased tumor neoantigens and tumor mutation burdens, and consequent exacerbation of immune responses, particularly the enrichment of M1-like macrophages in HGSOC cases.

Previously preclinical models for customized drug screening and precision oncology are being developed to replace animal models. Advances in biocompatible organoid technology have made it possible to culture cancer organoids from human tumor tissues. Cancer organoids are easy to proliferate, and large-scale drug screening platforms can be developed in that they can reproducibly repeat experiments with various concentrations of drugs. In this study, we developed automated extracellular matrix integrated, three-dimensional, patient-derived cell spotting technology and pillar-based cancer organoid culture system for anticancer drug screening platform as a preclinical model which able to contribute for prediction of therapeutic responses and selection of optimal next line anticancer drugs. In case of ovarian cancer, about 70-80% of patients are firstly diagnosed, but their 5-year survival rate is still under 50%. To increase the 5-year survival rate, raising therapeutic responses is urgently needed by effective drug treatment rather than standard therapy. For drugs selected through a drug screening platform to be applied to actual clinical practice, standard test methods must be set up, and clinical results and organoid-based treatment responses must be clearly compared and verified. For validation above, we confirmed the organoid on pillar-based drug testing platform by using surgical specimens from 109 ovarian cancer patients from SMC (Samsung medical center). Primary cells with extracellular matrix spotted and cultured on 384 pillar plates by ASFA spotter (MBD Inc.). After organoid formation on pillars, anticancer drug screening was performed for 14 drug combinations using cancer organoids derived from the ascites of patients. Cell viabilities and drug responses were calculated by ATP measurement and staining of intracellular Calcein then. Particularly in this study, parallel with drug treatment, organoid growth rate was measured by comparing the average areas, processed by ASFA cell analyzer (MBD Inc.), of organoids at drug treatment and termination day. Finally anticancer drug sensitivity index was calculated by combination of the drug response of AUC and respective organoid growth rate, then it was verified by matching with the clinical responses of 1st chemotherapies after surgery. As a results, the drug susceptibility index was predicted patients of recurrence within 6-month after 1st chemotherapy by our drug screening platform with increased sensitivity and specificity. This anticancer drug screening platform raised the recurrence prediction about 90% compared to existing drug sensitivity index such as IC50 or AUC, and through this, this platform could contribute to precision medicine in ovarian cancer patients. Therefore, it can be preclinical model used to screen the optimal drug for customized treatment using patient-specific individual organoids. Citation Format: Hye Ryeong Jun, Sung Hun Ju, Jung Eun Kim, Dong Woo Lee, Bosung Ku, Joseph Noh, Jeogn-Won Lee, Hyun Ju Kang, Jin-Ku Lee. Organo-on-pillar based anticancer drug screening platform for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 762.

Axitinib, small molecule tyrosine kinase inhibitor, demonstrates anti-cancer activity for various solid tumors. We investigated anti-cancer effect of axitinib in epithelial ovarian cancer (EOC). We treated EOC cells (A2780, HeyA8, RMG1, and HeyA8-MDR) with axitinib to evaluate its effects on cell viabilty, apoptosis and migration. Western blots were performed to assess VEGFR2, ERK, and AKT levels, and ELISA and FACS to evaluate apoptosis according to axitinib treatment. In addition, in vivo experiments in xenografts using A2780, RMG1, and HeyA8-MDR cell lines were performed. We repeated the experiment with patient-derived xenograft models (PDX) of EOC. Axitinib significantly inhibited cell survival and migration, and increased apoptosis in EOC cells. The expression of VEGFR2 and phosphorylation of AKT and ERK in A2780, RMG1, and HeyA8 were decreased with axitinib treatment in dose-dependent manner, but not in HeyA8-MDR. In in vivo experiments, axitinib significantly decreased tumor weight in xenograft models of drug-sensitive (A2780), and clear cell carcinoma (RMG1) and PDX models for platinum sensitive EOC compared to control, but was not effective in drug-resistant cell line (HeyA8-MDR) or heavily pretreated refractory PDX model. Axitinib showed significant anti-cancer effects in drug-sensitive or clear cell EOC cells via inhibition of VEGFR signals associated with cell proliferation, apoptosis and migration, but not in drug-resistant cells.

Glioblastoma (GBM) is the most lethal primary brain tumor with few treatment options. The survival of glioma-initiating cells (GICs) is one of the major factors contributing to treatment failure. GICs frequently produce and respond to their own growth factors that support cell proliferation and survival. In this study, we aimed to identify critical autocrine factors mediating GIC survival and to evaluate the anti-GBM effect of antagonizing these factors. Proteomic analysis was performed using conditioned media from two different patient-derived GBM tumor spheres under a growth factor-depleted status. Then, the antitumor effects of inhibiting an identified autocrine factor were evaluated by bioinformatic analysis and molecular validation. Proteins secreted by sphere-forming GICs promote cell proliferation/survival and detoxify reactive oxygen species (ROS). Among these proteins, we focused on midkine (MDK) as a clinically significant and pathologically relevant autocrine factor. Antagonizing MDK reduced the survival of GBM tumor spheres through the promotion of cell cycle arrest and the consequent apoptotic cell death caused by oxidative stress-induced DNA damage. We also identified PCBP4, a novel molecular predictor of resistance to anti-MDK treatment. Collectively, our results indicate that MDK inhibition is an important therapeutic option by suppressing GIC survival through the induction of ROS-mediated cell cycle arrest and apoptosis., Brain cancer: a key growth factor Targeting the growth factor midkine (MDK) may offer improved treatment for glioblastoma, the most lethal brain cancer. In glioblastoma, the tumor-initiating cells produce their own growth factors, encouraging themselves to keep multiplying, and making glioblastoma very difficult to treat. Do-Hyun Nam and Hyun Ju Kang at the Samsung Medical Center, Seoul, South Korea and coworkers screened the growth factors produced by two glioblastoma samples, then focused on a single cancer-associated factor, MDK. Antagonizing MDK slowed tumor cell growth, and further investigation showed that suppressing MDK restored the susceptibility of tumor cells to DNA damage and the mechanisms that weed out damaged cells. Noting that treatment efficacy varied between tumor samples, the researchers identified a biomarker for sensitivity to MDK treatment. These results point the way to new treatments for this particularly deadly cancer.

Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical relevance remain unexplored in GBM. We discovered that PIP4K2A negatively regulates phosphoinositide 3-kinase (PI3K) signaling via p85/p110 component degradation in PTEN-deficient GBMs and specifically targets p85 for proteasome-mediated degradation. Overexpression of PIP4K2A suppressed cellular and clonogenic growth in vitro and impeded tumor growth in vivo. Our results unravel a novel tumor-suppressive role of PIP4K2A for the first time and support the feasibility of combining oncogenomics with in vivo RNAi screen.

Background Cancer is a complex disease with profound genomic alterations and extensive heterogeneity. Recent studies on large-scale genomics have shed light on the impact of core oncogenic pathways, which are frequently dysregulated in a wide spectrum of cancer types. Aberrant activation of the hepatocyte growth factor (HGF) signaling axis has been associated with promoting various oncogenic programs during tumor initiation, progression, and treatment resistance. As a result, HGF-targeted therapy has emerged as an attractive therapeutic approach. However, recent clinical trials involving HGF-targeted therapies have demonstrated rather disappointing results. Thus, an alternative, in-depth assessment of new patient stratification is necessary to shift the current clinical course. Methods To address such challenges, we have evaluated the therapeutic efficacy of YYB-101, an HGF-neutralizing antibody, in a series of primary glioblastoma stem cells (GSCs) both in vitro and in vivo. Furthermore, we performed genome and transcriptome analysis to determine genetic and molecular traits that exhibit therapeutic susceptibility to HGF-mediated therapy. Results We have identified several differentially expressed genes, including MET, KDR, and SOX3, which are associated with tumor invasiveness, malignancy, and unfavorable prognosis in glioblastoma patients. We also demonstrated the HGF-MET signaling axis as a key molecular determinant in GSC invasion, and we discovered that a significant association in HGF expression existed between mesenchymal phenotype and immune cell recruitment. Conclusions Upregulation of MET and mesenchymal cellular state are essential in generating HGF-mediated therapeutic responses. Our results provide an important framework for evaluating HGF-targeted therapy in future clinical settings.

Precision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies. However, this proposition is complicated by spatial and temporal heterogeneity. Here we study genomic and expression profiles across 127 multisector or longitudinal specimens from 52 individuals with glioblastoma (GBM). Using bulk and single-cell data, we find that samples from the same tumor mass share genomic and expression signatures, whereas geographically separated, multifocal tumors and/or long-term recurrent tumors are seeded from different clones. Chemical screening of patient-derived glioma cells (PDCs) shows that therapeutic response is associated with genetic similarity, and multifocal tumors that are enriched with PIK3CA mutations have a heterogeneous drug-response pattern. We show that targeting truncal events is more efficacious than targeting private events in reducing the tumor burden. In summary, this work demonstrates that evolutionary inference from integrated genomic analysis in multisector biopsies can inform targeted therapeutic interventions for patients with GBM.

Background Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Comprehensive genomic analysis has revealed a list of molecular aberrations that are essential to tumorigenesis, progression, and metastasis of gynecologic tumors. However, targeting such alterations has frequently led to treatment failures due to underlying genomic complexity and simultaneous activation of various tumor cell survival pathway molecules. A compilation of molecular characterization of tumors with pharmacological drug response is the next step toward clinical application of patient-tailored treatment regimens. Results Toward this goal, we establish a library of 139 gynecologic tumors including epithelial ovarian cancers (EOCs), cervical, endometrial tumors, and uterine sarcomas that are genomically and/or pharmacologically annotated and explore dynamic pharmacogenomic associations against 37 molecularly targeted drugs. We discover lineage-specific drug sensitivities based on subcategorization of gynecologic tumors and identify TP53 mutation as a molecular determinant that elicits therapeutic response to poly (ADP-Ribose) polymerase (PARP) inhibitor. We further identify transcriptome expression of inhibitor of DNA biding 2 (ID2) as a potential predictive biomarker for treatment response to olaparib. Conclusions Together, our results demonstrate the potential utility of rapid drug screening combined with genomic profiling for precision treatment of gynecologic cancers.

Staphylococcus aureus enterotoxin (SAE) superantigens are detected in nasal polyps (NPs), and SAE-specific IgE predicts asthma comorbidity in patients with NPs. However, roles of SAE superantigens and superantigen-related T-cell responses remain to be elucidated in nonasthmatic patients.We investigated the presence of SAEs and SAE-related T-cell receptor (TCR) Vβ (TCRVβ) in nonasthmatic NPs, the phenotypes and functions of SAE-related T cells, and the clinical implication of SAE-related T-cell expansion.Sinonasal tissue samples were obtained from patients with nonasthmatic chronic rhinosinusitis (CRS) with NPs (CRSwNP), patients with CRS without NPs (CRSsNP), and control subjects. SAE genes were detected by PCR, and the TCRVβ distribution and T-cell phenotypes were examined by flow cytometry.Various SAE genes were detected not only in NPs but also in sinonasal mucosa from patients with CRSsNP and from controls. The S aureus enterotoxin I (SEI) gene was detected in all NPs. The fraction of SEI-responsive TCRVβIn nonasthmatic patients with CRSwNP, superantigen-related expansion of CD4

Additional file 1: Figure S1. Frequency of major cancer-driver gene alterations in gynecologic tumors. Figure S2. Frequency of major cancer-driver genes in SMC and TCGA cohorts. Figure S3. Drug panel classification. Figure S4. Preservation of copy number alterations in primary tissues and PDCs. Figure S5. Representation of histopathologic characteristics between parental and patient-derived xenograft tumors. Figure S6. Pharmacological landscape of 37 molecular-targeted agents. Figure S7. Frequency of major cancer-driver gene alterations in ovarian cancer.

WNTs and their downstream effectors regulate proliferation, death, and migration and cell fate decision. Deregulation of WNT signaling is associated with various cancers including GBM, which is the most malignant primary brain cancer. In this review, we will summarize the experimental evidence supporting oncogenic roles of WNT signaling in GBM and discuss current progress in the targeting of WNT signaling as an anti-cancer approach. In particular, we will focus on (1) genetic and epigenetic alterations that lead to aberrant WNT pathway activation in GBM, (2) WNT-mediated control of GBM stem cell maintenance and invasion, and (3) cross-talk between WNT and other signaling pathways in GBM. We will then review the discovery of agents that can inhibit WNT signaling in preclinical models and the current status of human clinical trials.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background Staphylococcus aureus enterotoxin (SAE) superantigens are detected in nasal polyps (NPs), and SAE-specific IgE predicts asthma comorbidity in patients with NPs. However, roles of SAE superantigens and superantigen-related T-cell responses remain to be elucidated in nonasthmatic patients. Objective We investigated the presence of SAEs and SAE-related T-cell receptor (TCR) Vβ (TCRVβ) in nonasthmatic NPs, the phenotypes and functions of SAE-related T cells, and the clinical implication of SAE-related T-cell expansion. Methods Sinonasal tissue samples were obtained from patients with nonasthmatic chronic rhinosinusitis (CRS) with NPs (CRSwNP), patients with CRS without NPs (CRSsNP), and control subjects. SAE genes were detected by PCR, and the TCRVβ distribution and T-cell phenotypes were examined by flow cytometry. Results Various SAE genes were detected not only in NPs but also in sinonasal mucosa from patients with CRSsNP and from controls. The S aureus enterotoxin I (SEI) gene was detected in all NPs. The fraction of SEI–responsive TCRVβ+ (TCRVβ1+ and Vβ5.1+) CD4+ T cells was significantly increased only in NPs and the ethmoidal mucosa of patients with CRSwNP, indicating superantigen-induced expansion. The expanded TCRVβ5.1+ CD4+ T cells expressed proliferation marker Ki-67 and the TH2 transcription factor GATA3. Furthermore, TCRVβ5.1+ CD4+ T cells in NPs highly expressed TH2 markers, including IL-17RB, thymic stromal lymphoprotein receptor, and chemoattractant receptor–homologous molecule expressed on TH2 cells, with a potent TH2 cytokine–producing ability. Moreover, the expansion of TCRVβ1+ or Vβ5.1+ CD4+ T cells was associated with the Lund-Mackay computed tomography score, indicating disease extent. Conclusion In nonasthmatic patients with CRSwNP, superantigen-related expansion of CD4+ T cells with TH2 differentiation was associated with the disease extent.

Diffusely infiltrating gliomas (DIGs) are difficult to completely resect and are associated with a high rate of tumor relapse and progression from low- to high-grade glioma. In particular, optimized short-term culture-enriching patient-derived glioma stem cells (GSCs) are essential for customizing the therapeutic strategy based on clinically feasible in vitro drug screening for a wide range of DIGs, owing to the high inter-tumoral heterogeneity. Herein, we constructed a novel high-throughput culture condition screening platform called &lsquo, GFSCAN&rsquo, which evaluated the cellular growth rates of GSCs for each DIG sample in 132 serum-free combinations, using 13 previously reported growth factors closely associated with glioma aggressiveness. In total, 72 patient-derived GSCs with available genomic profiles were tested in GFSCAN to explore the association between cellular growth rates in specific growth factor combinations and genomic/molecular backgrounds, including isocitrate dehydrogenase 1 (IDH1) mutation, chromosome arm 1p and 19q co-deletion, ATRX chromatin remodeler alteration, and transcriptional subtype. GSCs were clustered according to the dependency on epidermal growth factor and basic fibroblast growth factor (E&amp, F), and isocitrate dehydrogenase 1 (IDH1) wild-type GSCs showed higher E&amp, F dependencies than IDH1 mutant GSCs. More importantly, we elucidated optimal combinations for IDH1 mutant glioblastoma and lower grade glioma GSCs with low dependencies on E&amp, F, which could be an aid in clinical decision-making for these DIGs. Thus, we demonstrated the utility of GFSCAN in personalizing in vitro cultivation to nominate personalized therapeutic options, in a clinically relevant time frame, for individual DIG patients, where standard clinical options have been exhausted.

Outcomes of anticancer therapy vary dramatically among patients due to diverse genetic and molecular backgrounds, highlighting extensive inter-tumoral heterogeneity. The fundamental tenet of precision oncology defines molecular characterization of tumors to guide optimal patient-tailored therapy. Towards this goal, we have established a compilation of pharmacological landscape of 462 patient-derived tumor cells (PDCs) across 14 cancer types, together with genomic and transcriptomic profiling in 385 of these tumors. Compared to the traditional long-term cultured cancer cell-line models, PDCs recapitulate the molecular properties and biology of the diseases more precisely. In present study, we provide unprecedented insights into dynamic pharmacogenomic associations, including molecular determinants that elicit therapeutic resistance to EGFR inhibitors and potential repurposing of ibrutinib (currently being used in hematological malignancies) for EGFR-specific therapy in gliomas. Lastly, we present potential implementation of PDC-derived drug sensitivities for prediction of clinical response to targeted therapeutics using retrospective clinical studies.

Background Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed. Methods We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells. Results USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice. Conclusion USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM.

Glioblastoma (GBM) is the most lethal brain cancer with profound genomic alterations. While the bona fide tumor suppressor genes such as PTEN, NF1, and TP53 have high frequency of inactivating mutations, there may be the genes with GBM-suppressive roles for which genomic mutation is not a primary cause for inactivation. To identify such genes, we employed in vivo RNAi screening approach using the patient-derived GBM xenograft models. We found that Nemo-Like Kinase (NLK) negatively regulates mesenchymal activities, a characteristic of aggressive GBM, in part via inhibition of WNT/β-catenin signaling. Consistent with this, we found that NLK expression is especially low in a subset of GBMs that harbors high WNT/mesenchymal activities. Restoration of NLK inhibited WNT and mesenchymal activities, decreased clonogenic growth and survival, and impeded tumor growth in vivo. These data unravel a tumor suppressive role of NLK and support the feasibility of combining oncogenomics with in vivo RNAi screen.

Shin et al. identify PIP4K2A as a putative tumor suppressor in glioblastoma using an in vivo RNAi screen system. PIP4K2A competes with PTEN to negatively regulate PI3K signaling via p85/p110 component degradation in vitro and in vivo, and its expression is significantly down-regulated in GBM patients., Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical relevance remain unexplored in GBM. We discovered that PIP4K2A negatively regulates phosphoinositide 3-kinase (PI3K) signaling via p85/p110 component degradation in PTEN-deficient GBMs and specifically targets p85 for proteasome-mediated degradation. Overexpression of PIP4K2A suppressed cellular and clonogenic growth in vitro and impeded tumor growth in vivo. Our results unravel a novel tumor-suppressive role of PIP4K2A for the first time and support the feasibility of combining oncogenomics with in vivo RNAi screen., Graphical Abstract

GBM is the most aggressive human primary brain tumor and leads to poor clinical outcomes. According to previous studies, exogenous factors secreted from primary brain tumor cells can change the growth pattern of normal cells. We analyzed the ingredients of cell culture media from two patient glioblastoma cells which can grow without growth factors. As a result, we selected a significant factor for tumor cell growth which is called cytokine A, the Heparin-binding growth factor. Because of the cell viability maintenance ability of cytokine A, we tried to investigate detailed mechanism of cytokine A and applied the result to the combination therapy. Cytokine A is critical for tumorigenesis of GBM by modulating DNA damage signaling and cell cycle through ROS. For that reason, cytokine A is effective therapeutic target and can be used in combination therapy.

Glioblastoma multiforme (GBM) is the most common human primary brain malignancy and has a dismal prognosis. Aggressive treatments using maximal surgical resection, radiotherapy, and temozolomide result in median survival of only 14.6 months in patients with GBM. Numerous clinical approaches using small molecule inhibitors have shown disappointing results because of the genetic heterogeneity of GBM. The epithelial to mesenchymal transition (EMT) is a crucial biological process occurring in the early development stages of many species. However, cancer cells often obtain the ability to invade and metastasize through the EMT, which triggers the scattering of cells. The hepatocyte growth factor (HGF)/MET signaling pathway is indicative of the EMT during both embryogenesis and the invasive growth of tumors, because HGF potently induces mesenchymal transition in epithelial-driven cells. Activation of MET signaling or co-overexpression of HGF and MET frequently represents aggressive growth and poor prognosis of various cancers, including GBM. Thus, efforts to treat cancers by inhibiting MET signaling using neutralizing antibodies or small molecule inhibitors have progressed during the last decade. In this review, we discuss HGF/MET signaling in the development of diseases, including cancers, as well as updates on MET inhibition therapy.

Recently, obesity is a complex multifactorial chronic disease increasing the risk for type 2 diabetes, coronary heart disease and hypertension, and has become a major worldwide health problem. In the course of screening natural products employing 3T3-L1 cells as an in vitro system, the methanol extract of Idesia polycarpa Maxim. Fruits (Flacourtiaceae) significantly inhibited adipocyte differentiation by measuring lipid contents using oil red O staining. One new compound, 6-(oxymethyl)-2-hydroxyphenyl- O -β- d -glucopyranosyl-(1 → 6)-β- d -glucopyranoside ( 8 ), was isolated along with nine known compounds ( 1 – 7 and 9 – 10 ) from CHCl 3 and n -BuOH fractions of the methanol extract of I . polycarpa fruits. Among them, idescarpin ( 1 ) with 1-hydroxy-6-oxo-2-cyclohexenecarboxylate moiety showed the most potent inhibitory activity on adipocyte differentiation with IC 50 values of 23.2 μM. Idescarpin ( 1 ) dramatically suppressed the induction of C/EBPα expression, whereas it significantly increased the induction of PPARγ expression, supported by quantitative real time PCR and Western blot analysis. The down-regulation in mRNA levels of SREBP1c, SCD-1, and FAS by idescarpin ( 1 ) during adipocyte differentiation revealed that the inhibition of adipocyte differentiation was mediated by the regulation of lipogenesis. Taken together, we suggest that idescarpin ( 1 ) shows a great potential against obesity and diabetes though the anti-adipogenic activity and the up-regulation of PPARγ.

Bone marrow stromal cell antigen 2 (BST-2) is a type II transmembrane protein that is known to be a therapeutic target in several types of cancer. However, despite its clinical importance, the roles of BST-2 expression have remained elusive. Here, we found that BST-2 expression is up-regulated in tamoxifen-resistant MCF-7 human breast cancer (TRM-7) cells, resulting in enhanced invasiveness and migration. Matrigel and wound healing assays also showed that overexpression of BST-2 increased invasion and migration in MCF-7 cells, whereas invasion and migration were decreased by the silencing of BST-2 in TRM-7 cells. In addition, B16F10 cells expressing BST-2 showed increased metastatic melanoma nodule growth in a lung metastasis mouse model. Furthermore, BST-2 expression and promoter activity were regulated by activated signal transducer and activator of transcription 3 (STAT3). Taken together, our results indicate that BST-2 is an important factor in the invasiveness and motility of tamoxifen-resistant breast cancer cells, and that its expression and activity are regulated by activated STAT3. Therefore, regulation of BST-2 is a potential therapeutic target for tamoxifen-resistant breast cancer.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by the oxidative burst in activated macrophages and neutrophils cause oxidative stress-implicated diseases. Quercetin is flavonoid that occurs naturally in plants and is widely used as a nutritional supplement due to its antioxidant and anti-inflammatory properties. In this study, we investigated antioxidant activities and mechanisms of action in zymosan-induced macrophages of quercetin and quercetin-related flavonoids such as quercitrin, isoquercitrin, quercetin 3-O-β-(2″-galloyl)-rhamnopyranoside (QGR) and quercetin 3-O-β-(2″-galloyl)-glucopyranoside (QGG) as well as gallic acid, a building moiety of QGR and QGG. QGR and QGG exhibited stronger antioxidant activities compared with quercetin, whereas quercitrin, isoquercitrin and gallic acid exhibited weak-to-no antioxidant activities, assessed by 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging, superoxide production, superoxide scavenging, nitric oxide (NO) production, peroxynitrite (ONOO−) scavenging and myeloperoxidase (MPO) activity. Regarding mechanisms, the quercetin-containing flavonoids QGR and QGG differentially targeted compared with quercetin in the NF-κB signaling pathway that inhibited the DNA binding activity of the NF-κB complex without affecting the degradation and phosphorylation of IκBα and NF-κB phosphorylation. In addition, QGR and QGG inhibited CRE and activator protein (AP-1) transcriptional activity and JNK phosphorylation by inhibiting the cAMP/protein kinase A (PKA) and protein kinase C (PKC) signaling in a different manner than quercetin. Our results showed that although QGR and QGG exhibited stronger antioxidant activities than quercetin in macrophages, their mechanisms of action in terms of the NF-κB, PKA and PKC signaling pathways were different.

Background Skin is uniquely vulnerable to damage caused by reactive oxygen species (ROS), which are most commonly produced in response to ultraviolet (UV) light. ROS generated at injury sites play an important role in modulating the inflammatory response. Besides inhibiting Rac, 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxo-dG) has also shown notable antioxidant action. Objective We tested whether 8-oxo-dG could protect skin from UVB-induced damage by scavenging ROS. Methods HaCaT cells and hairless mice were irradiated with 15 and 180 mJ/cm 2 narrow-spectrum UVB, respectively. ROS generation was detected through incubation with DCFDA and confocal microscopy. Western blot analyses and immunohistochemistry were performed to verify the activities of ERK, JNK, p38, ATF-2, and c-Jun, and the expression of matrix metalloproteinases (MMPs), in UVB-irradiated HaCaT cells and murine skin. Hydrogen peroxide production and protein carbonyl concentrations were measured in UVB-damaged mouse skin. MMP-1 and MMP-9 expression in UVB-irradiated HaCaT cells was measured by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Results In UVB-irradiated HaCaT cells, 8-oxo-dG inhibited ROS production, subsequent activation of mitogen-activated protein kinase (MAPK), ATF-2, and c-Jun, and MMP expression. It also prevented UV-induced skin reactions in hairless mice, inhibiting the increase in protein carbonyl content, activation of MAPKs, ATF-2, and c-Jun, the increases in MMP-9 and -13 expression, and epidermal hyperplasia. Conclusion 8-oxo-dG can be considered an endogenous antioxidant and its potent antioxidant activity might be a beneficial property that could be exploited to protect skin from ROS-associated photodamage.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. To better understand how GBM evolves, we analyzed longitudinal genomic and transcriptomic data from 114 patients. The analysis shows a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern, together with estimates of evolutionary rate, suggests that relapse-associated clones typically existed years before diagnosis. Fifteen percent of tumors present hypermutation at relapse in highly expressed genes, with a clear mutational signature. We find that 11% of recurrence tumors harbor mutations in LTBP4, which encodes a protein binding to TGF-β. Silencing LTBP4 in GBM cells leads to suppression of TGF-β activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-β pathway as a potential therapeutic target in GBM.

We previously reported that 8-oxo-2'-deoxyguanosine (8-oxo-dG) suppressed airway hyperresponsiveness and allergy-associated immune responses in ovalbumin-induced allergic mice by inactivating Rac. In the present study, 8-oxo-dG was investigated for its suppression of inflammation and remodeling in lung tissues induced by allergic reaction in mice. Mice were sensitized and challenged with ovalbumin without or with oral administration of 8-oxo-dG. The mice without 8-oxo-dG administration showed the following inflammatory and airway remodeling signs: infiltration of inflammatory cells into peribronchial area, hyperplasia of mucus-secreting goblet cells in bronchial walls, increase of expressions of Muc5ac and vascular cell adhesion molecule (VCAM)-1, collagen deposition and protein expression, and matrix metalloproteinase (MMP)-2/-9 expressions. We also observed an increase of various inflammation-mediating proteins, namely IL-4, IL-5, IL-8, IL-13, TNF-α and IFN-γ, and activation of STAT1 and NF-κB. Production of reactive oxygen species and nitric oxide (NO(.)) was increased as indicated by a dramatic increase in formation of nitro-tyrosine. Importantly, Rac1 and 2 were also markedly activated. However, 8-oxo-dG suppressed all these inflammatory and tissue remodeling signs as well as activation of Rac1 and 2. These results indicate that 8-oxo-dG can inhibit allergy-induced inflammation and remodeling in airway and lung tissues through Rac inactivation.

GBM is the most aggressive human primary brain tumor and leads to poor clinical outcomes. According to previous studies, exogenous factors secreted from primary brain tumor cells can change the growth pattern of normal cells. We analyzed the ingredients of cell culture media from two patient glioblastoma cells which can grow without growth factors. As a result, we selected a significant factor for tumor cell growth which is called cytokine A, the Heparin-binding growth factor. Because of the cell viability maintenance ability of cytokine A, we tried to investigate detailed mechanism of cytokine A and applied the result to the combination therapy. Cytokine A is critical for tumorigenesis of GBM by modulating DNA damage signaling and cell cycle through ROS. For that reason, cytokine A is effective therapeutic target and can be used in combination therapy. Citation Format: Suji Han, Kayoung Shin, Kyoungmin Lee, Sungsoo Kim, Hyunju Kang, Jin-Ku Lee, Hyun Nam, Kyeung Min Joo, Do-Hyun Nam. Patient GBM cell originated secretome analysis identifies cytokine A, as a potent therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2521.

A plasma-doping (PLAD) process utilizing a PH3 plasma is presented to fabricate a n /p ultrashallow junction at room temperature. When PLAD is completed, an excimer laser annealing (ELA) process is performed using an ArF (193 nm) excimer laser with pre-annealing. In our case, the preannealing is conducted for 5 min at 500 ◦C in a thermal furnace. The energy density of the excimer laser used for the ELA process ranged from 400 to 500 mJ/cm. Transmission electron microscope (TEM) and double-crystal X-ray diffraction (DXRD) measurements were employed to investigate defects on the plasma-doped samples. Some point defects were found in the DXRD analysis while TEM images reveal no crystalline defects. The result of a secondary ion mass spectrometry (SIMS) analysis on the formed shallow n/p junction revealed that the junction depth was thinner than 40 nm. We found that the drive-in process of phosphorous occurred only when the energy density of the laser was larger than 460 mJ/cm, and an increased laser energy density resulted in a decreased sheet resistance. With an energy density of 460 mJ/cm, a junction depth of 30 nm and a sheet resistance of 151.6 Ω/ were obtained. The leakage current for the fabricated n/p junction was indirectly investigated by measuring the I-V characteristics of the diode fabricated using PLAD, followed by the ELA processes.

Metabolic syndrome describes a group of clinical features that together increase the incidence of coronary artery disease, stroke and type 2 diabetes. Insulin resistance is a major risk factor for developing metabolic syndrome. A chronic state of inflammation accompanies the accumulation of surplus lipids in adipose and liver tissue, frequently involved in insulin resistance. 8-Oxo-2'-deoxyguanosine (8-Oxo-dG) is a potent anti-inflammatory agent that inactivates both Rac1 and Rac2 which are critical to initiating the inflammatory responses in various cell types, including macrophages. In this study, we explored whether 8-Oxo-dG suppressed a series of systemic inflammatory cascades, resulting in the amelioration of typical features of metabolic syndrome in obese mice. The results demonstrate that 8-Oxo-dG effectively improved hyperglycemia, dyslipidemia and fatty liver changes in obese mice. The level of biochemical markers indicative of systemic inflammation were reduced in 8-Oxo-dG treated mice, whereas serum levels of adiponectin, a crucial factor associated with improved metabolic syndrome, were enhanced. Our results demonstrate that 8-Oxo-dG effectively disrupts the pathogenesis of insulin resistance and obesity-associated metabolic syndrome.

The naive T-cell pool in peripheral lymphoid tissues is fairly stable in terms of number, diversity and functional capabilities in spite of the absence of prominent stimuli. This stability is attributed to continuous tuning of the composition of the T-cell pool by various homeostatic signals. Despite extensive research into the link between signal transducer and activator of transcription 3 (Stat3) and T-cell survival, little is known about how Stat3 regulates homeostasis by maintaining the required naive T-cell population in peripheral lymphoid organs. We assessed whether the elimination of Stat3 in T cells limits T-cell survival. We demonstrated that the proportion and number of single-positive thymocytes as well as T cells in the spleen and lymph nodes were significantly decreased in the Stat3-deficient group as a result of the enhanced susceptibility of Stat3-deleted T lymphocytes to apoptosis. Importantly, expression of the anti-apoptotic Bcl-2 and Bcl-xL was markedly decreased in Stat3-deleted single-positive thymocytes and T lymphocytes, suggesting that Stat3 helps to maintain the T-cell pool in the resting condition by promoting the expression of Bcl-2 family genes. These findings suggest the importance of Stat3 in the integration of homeostatic cues for the maintenance and functional tuning of the T-cell pool.

The acquisition of tamoxifen resistance is a major therapeutic problem in breast cancer. We developed a tamoxifen-resistant MCF-7 (TRM-7) cell line to elucidate the molecular mechanisms and factors associated with acquisition of such resistance. We showed that phosphorylation of STAT3 at tyrosine 705 (Y705) and RANTES expression are increased in response to tamoxifen in human breast cancer cells. On the basis of these results, we hypothesize that upregulated STAT3 phosphorylation and RANTES may be correlated with the development of drug resistance. Here, we showed that STAT3 and RANTES contribute to the maintenance of drug resistance. STAT3 phosphorylation is constitutively retained via a RANTES autocrine loop, which in turn upregulates anti-apoptotic signals in TRM-7 cells. STAT3–RANTES autocrine signaling affected expression of anti-apoptotic BCL-2 family genes and prevented TRM-7 cells from undergoing programmed cell death by inhibiting PARP and caspase-9 cleavage. Subsequently, blockade of STAT3 and RANTES in TRM-7 cells resulted in reduction of anti-apoptotic signals, which was rescued by exogenous RANTES treatment; drug resistance was also restored. Taken together, our results suggested that STAT3–RANTES autocrine signaling is essential for maintenance of drug resistance and inhibition of programmed cell death. These mechanisms of STAT3–RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors. Mol Cancer Res; 11(1); 31–42. ©2012 AACR . This article is featured in Highlights of This Issue, [p. 1][1] [1]: /lookup/volpage/11/1?iss=1

Recently, statins have been shown to have anti-inflammatory effects on lung inflammatory diseases. However, the mechanisms of action of simvastatin in viral pneumonia have yet to be elucidated, although viral infection remains a considerable health threat. In this study, we hypothesised that simvastatin inhibits polyinosinic-polycytidylic acid (poly I:C)-induced airway inflammation, such as RANTES (regulated on activation, normal T-cell expressed and secreted) expression and inflammatory cell recruitment. In bronchial cells, the effect of simvastatin on poly I:C-induced RANTES expression and signal transducer and activator of transcription (STAT)3-mediated signal transduction was determined using an ELISA and short hairpin (sh)RNA system. In a poly I:C-induced pneumonia mouse model, immunological changes in the lungs after simvastatin inhalation, such as inflammatory cell recruitment and cytokine/chemokine release, were examined. In poly I:C-stimulated bronchial cells, RANTES secretion was increased by STAT3 activation, and simvastatin suppressed poly I:C-induced STAT3 activation, resulting in inhibition of RANTES expression. In BALB/c mice stimulated with inhaled poly I:C, RANTES expression and neutrophil infiltration into the airway were elevated. However, simvastatin treatment attenuated STAT3 activation, RANTES release and subsequent neutrophilia in the lungs. These findings suggest that simvastatin inhibits airway inflammation, but there are other mechanisms that need to be fully elucidated.

Background Intestinal epithelium is essential for maintaining normal intestinal homeostasis; its breakdown leads to chronic inflammatory pathologies, such as inflammatory bowel diseases (IBDs). Although high concentrations of S100A9 protein and interleukin-6 (IL-6) are found in patients with IBD, the expression mechanism of S100A9 in colonic epithelial cells (CECs) remains elusive. We investigated the role of IL-6 in S100A9 expression in CECs using a colitis model. Methods IL-6 and S100A9 expression, signal transducer and activator of transcription 3 (STAT3) phosphorylation, and infiltration of immune cells were analyzed in mice with dextran sulfate sodium (DSS)-induced colitis. The effects of soluble gp130-Fc protein (sgp130Fc) and S100A9 small interfering (si) RNA (si-S100A9) on DSS-induced colitis were evaluated. The molecular mechanism of S100A9 expression was investigated in an IL-6-treated Caco-2 cell line using chromatin immunoprecipitation assays. Results IL-6 concentrations increased significantly in the colon tissues of DSS-treated mice. sgp130Fc or si-S100A9 administration to DSS-treated mice reduced granulocyte infiltration in CECs and induced the down-regulation of S100A9 and colitis disease activity. Treatment with STAT3 inhibitors upon IL-6 stimulation in the Caco-2 cell line demonstrated that IL-6 mediated S100A9 expression through STAT3 activation. Moreover, we found that phospho-STAT3 binds directly to the S100A9 promoter. S100A9 may recruit immune cells into inflamed colon tissues. Conclusions Elevated S100A9 expression in CECs mediated by an IL-6/STAT3 signaling cascade may play an important role in the development of colitis.

The initiation and growth of hepatocellular carcinoma (HCC) are closely linked to chronic inflammation. Not only is cyclin D1 overexpressed, but it is also related to aggressive progression in HCC. However, the mechanism of expression cyclin D1, a cell-cycle regulator of paramount importance, in the tumor microenvironment remains unknown. Here, we investigated the mechanism of cyclin D1 expression induced by interleukin-6 (IL-6) and whether 3-[3,4-dihydroxy-phenyl]-acrylic acid 2-[3,4-dihydroxy-phenyl]-ethyl ester (CADPE), a derivate of caffeic acid, suppresses cyclin D1 expression. CADPE significantly inhibited IL-6-induced signal transducer and activator of transcription 3 (STAT3) activity in the Huh7 HCC cell line and attenuated IL-6-induced cyclin D1 transcription. Moreover, overexpression of constitutively active STAT3 increased cyclin D1 transcriptional activity and protein expression, whereas overexpression of a dominant-negative STAT3 deletion mutant (STAT3 (1-588)) reduced cyclin D1 transcriptional activity. In addition, CADPE effectively deacetylated histone 4 and prevented STAT3 recruitment to the cyclin D1 promoter, consistent with a role for the CADPE target, STAT3, in the regulation of cyclin D1 transcription. Collectively, these results indicate that CADPE suppresses cyclin D1 expression in HCC cells by blocking both IL-6-mediated STAT3 activation and recruitment of STAT3 to the cyclin D1 promoter.

Plasma doping (PLAD) process utilizing PH3 plasma to fabricate n-type junction with supplied bias of −1 kV and doping time of 60 sec under the room temperature is presented. The RTA process is performed at 900 °C for 10 sec. A defect-free surface is corroborated by TEM and DXRD analyses, and examined SIMS profiles reveal that shallow n+ junctions are formed with surface doping concentration of 1021atoms/cm3. The junction depth increases in proportion to the O2 gas flow when the N2 flow is fixed during the RTA process, resulting in a decreased sheet resistance. Measured doping profiles and the sheet resistance confirm that the n+ junction depth less than 52 nm and minimum sheet resistance of 313 Ω/□ are feasible.

Basic characteristics of ClusterBoron™ (B18H22) implantation were investigated for improving contact resistance in DRAM devices. Generally, 49BF2 has been widely used for contact implant application in DRAM manufacturing because of its higher productivity compared to monomer boron (11B). However, because of limited activation in a low thermal budget (∼800 °C) anneal, the sheet resistance was saturated for doses over 5×1015 ions/cm2. Although many investigations have been reported, such as 30BF implant mixed implant with monomer boron etc., no practical solution has been found for dramatic improvement of contact resistance in a productive manner. B18H22 was developed to overcome the productivity limitations encountered in low energy, high dose boron implantation and the limited activation of 49BF2 due to co‐implanted fluorine. In this study, basic characterization of the B18H22 contact implant was performed through sheet resistance, SIMS (Secondary Ion Mass Spectrometry) and XTEM (cross‐sectional transmission electron microscopy). The B18H22 implants showed lower sheet resistance than conventional 49BF2 for 5×1015 ions/cm2 on bare wafer tests. Through XTEM study, we found the activation behavior of both B18H22 and 49BF2 were directly related with the amorphous layer thickness and residual defects from low thermal budget anneal. PMOS contact resistance in the sub‐70 nm device by B18H22 implantation showed considerable improvement (about 30%), showing B18H22 could replace the BF2 for contact implant in contact resistance implant.

Implantation of B18H22 molecules at 80 keV and doses up to 4×1016 cm−2 were evaluated for the application of p‐type counterdoping of in situ n‐type doped polysilicon gates. Compared to conventional B implants, molecular implantation provides greatly improved throughput without the risk of energy contamination. Implants at these high doses resulted in poor re‐crystallization of the polysilicon layer due to the formation of excessive cluster‐type defects. Subjecting the polysilicon to either UV‐curing or low temperature soak annealing prior to dopant activation was not effective in improving the re‐crystallization process. However, breaking the dose into two portions at two different energies was shown to significantly improve re‐crystallization of the polysilicon layer. Improved dopant activation was confirmed by a >90% reduction in ring oscillator delay time on a 60 nm PMOSFET.

This paper discusses the formation of n-type shallow junctions using PH3 plasma doping technique. Shallow n+/p junctions are examined by secondary ion mass spectrometer (SIMS), transmission electron microscopy (TEM), double crystal X-ray diffraction (DXRD) and 4-point probe analysis methods. Measured doping profiles reveal that the junction depth less than 300 Aring and minimum sheet resistance of 104.1 Omega/I are feasible.

BACKGROUND: Tumor progression within a brain is the process of acquiring malignant genetic mutations from glial progenitor cells, dodging their original developmental fate and deteriorating functional connectivity of CNS. In order to devise effective targeted therapeutic strategies, understanding distinct molecular and phenotypic evolutionary features of cancer clones is eminent. METHODS: To examine molecular signatures associated with malignant glioma progression, we analyzed transcriptome dynamics of 311 single-cells derived from 3 patients showing distinct disease patterns. Combined with single-cell level signatures, clonal architecture of tumors was reconstructed based on Bayesian-model clustering with integrated information of SSNVs and SCNAs identified from bulk population-level using aCGH and WES. RESULTS: We found evidence of branched evolutionary patterns within and across two histopathological separated tumor regions. Both tumors have high clonal probable somatic mutations, and evolutionary inference showed clonal lineage between two tumor regions was divided at early time during tumor progression. For all patients, the gene expression signatures within a tumor were heterogeneous but converged towards mesenchymal phenotype in the aggressive region. In the first case, the left tumor was self-limiting and showed mixed proneural and classical gene expression signatures whereas the right side tumor has expanded to the corpus callosum with EGFR overexpression and mesenchymal gene expression. In a case of a monocentric tumor with PDGFRA amplification, cancer cells disseminated from the core mass with massive immune cell infiltration underwent transcriptome switching from proneural to mesenchymal gene expression, with a concomitant FGFR1 copy number gain and mutation. Lastly, in a secondary glioblastoma with IDH1 mutation, GLIOLAN positive glioblastoma was surrounded by grade III oligodendroglioma. The two tumor areas showed intermingled heterogeneous gene expression signatures, with upregulation of astrocytic/mesenchymal genes in the GLIOLAN positive tumor cells. CONCLUSIONS: Our results show distinct genetic patterns of clonal expansion across patients undergoing malignant glioma progression. We also provide the transcriptome-wide view of gene expression signatures directed by genomic alterations. Overall our study reveals heterogeneity of individual tumor but elucidates common genomic features of glioblastoma progression. Citation Format: Kyu-Tae Kim, Jin-Ku Lee, Dong-Hyun Park, Do-Hyun Nam, Hae-Ock Lee, Woong-Yang Park. Transcriptome landscape of brain tumor progression at single-cell resolution. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3748. doi:10.1158/1538-7445.AM2015-3748