An in silico screen links gene expression signatures to drug response in glioblastoma stem cells

2014 ◽  
Vol 15 (4) ◽  
pp. 347-353 ◽  
Author(s):  
G Riddick ◽  
H Song ◽  
S L Holbeck ◽  
W Kopp ◽  
J Walling ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
In Silico ◽  
Drug Response ◽  
Glioblastoma Stem Cells ◽  
Gene Expression Signatures

scholarly journals Drug response prediction by ensemble learning and drug-induced gene expression signatures

Genomics ◽  
2019 ◽  
Vol 111 (5) ◽  
pp. 1078-1088 ◽  
Author(s):  
Mehmet Tan ◽  
Ozan Fırat Özgül ◽  
Batuhan Bardak ◽  
Işıksu Ekşioğlu ◽  
Suna Sabuncuoğlu
Keyword(s):  
Gene Expression ◽  
Ensemble Learning ◽  
Drug Response ◽  
Response Prediction ◽  
Drug Induced ◽  
Gene Expression Signatures

scholarly journals Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 520 ◽  
Author(s):  
Ella L. Kim ◽  
Maxim Sorokin ◽  
Sven Rainer Kantelhardt ◽  
Darius Kalasauskas ◽  
Bettina Sprang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Drug Sensitivity ◽  
Recurrent Glioblastoma ◽  
Intratumor Heterogeneity ◽  
Glioma Stem Cells ◽  
Newly Diagnosed ◽  
Glioblastoma Stem Cells ◽  
Longitudinal Changes ◽  
Glioblastoma Recurrence

Background: Inevitable recurrence after radiochemotherapy is the major problem in the treatment of glioblastoma, the most prevalent type of adult brain malignancy. Glioblastomas are notorious for a high degree of intratumor heterogeneity manifest through a diversity of cell types and molecular patterns. The current paradigm of understanding glioblastoma recurrence is that cytotoxic therapy fails to target effectively glioma stem cells. Recent advances indicate that therapy-driven molecular evolution is a fundamental trait associated with glioblastoma recurrence. There is a growing body of evidence indicating that intratumor heterogeneity, longitudinal changes in molecular biomarkers and specific impacts of glioma stem cells need to be taken into consideration in order to increase the accuracy of molecular diagnostics still relying on readouts obtained from a single tumor specimen. Methods: This study integrates a multisampling strategy, longitudinal approach and complementary transcriptomic investigations in order to identify transcriptomic traits of recurrent glioblastoma in whole-tissue specimens of glioblastoma or glioblastoma stem cells. In this study, 128 tissue samples of 44 tumors including 23 first diagnosed, 19 recurrent and 2 secondary recurrent glioblastomas were analyzed along with 27 primary cultures of glioblastoma stem cells by RNA sequencing. A novel algorithm was used to quantify longitudinal changes in pathway activities and model efficacy of anti-cancer drugs based on gene expression data. Results: Our study reveals that intratumor heterogeneity of gene expression patterns is a fundamental characteristic of not only newly diagnosed but also recurrent glioblastomas. Evidence is provided that glioblastoma stem cells recapitulate intratumor heterogeneity, longitudinal transcriptomic changes and drug sensitivity patterns associated with the state of recurrence. Conclusions: Our results provide a transcriptional rationale for the lack of significant therapeutic benefit from temozolomide in patients with recurrent glioblastoma. Our findings imply that the spectrum of potentially effective drugs is likely to differ between newly diagnosed and recurrent glioblastomas and underscore the merits of glioblastoma stem cells as prognostic models for identifying alternative drugs and predicting drug response in recurrent glioblastoma. With the majority of recurrent glioblastomas being inoperable, glioblastoma stem cell models provide the means of compensating for the limited availability of recurrent glioblastoma specimens.

scholarly journals Oct1/Pou2f1 is selectively required for gut regeneration and regulates gut malignancy

2018 ◽  
Author(s):  
Karina Vázquez-Arreguín ◽  
Claire Bensard ◽  
John C. Schell ◽  
Eric Swanson ◽  
Xinjian Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Colon Cancer ◽  
Transcription Factor ◽  
Stem Cell ◽  
The United States ◽  
Mitotic Stability ◽  
Cell Compartments ◽  
Incidence And Mortality ◽  
Gene Expression Signatures

AbstractThe transcription factor Oct1/Pou2f1 promotes poised gene expression states, mitotic stability, glycolytic metabolism and other characteristics of stem cell potency. To determine the effect of Oct1 loss on stem cell maintenance and malignancy, we deleted Oct1 in two different mouse gut stem cell compartments. Oct1 deletion preserved homeostasis in vivo and the ability to generate cultured organoids in vitro, but blocked the ability to regenerate after treatment with dextran sodium sulfate, and the ability to maintain organoids after passage. In a chemical model of colon cancer, loss of Oct1 in the colon severely restricted tumorigenicity. In contrast, loss of one or bothOct1alleles progressively increased tumor burden in a colon cancer model driven by loss of heterozygosity of the tumor suppressor geneApc.The different outcomes are consistent with prior findings that Oct1 promotes mitotic stability, and consistent with different gene expression signatures associated with the two models. These results reveal that Oct1 is selectively required for gut regeneration, and has potent effects in colon malignancy, with outcome (pro-oncogenic or tumor suppressive) dictated by tumor etiology.Author summaryColorectal cancer is the second leading cause of cancer death in the United States. Approximately 35% of diagnosed patients eventually succumb to disease. The high incidence and mortality due to colon cancer demand a better understanding of factors controlling the physiology and pathophysiology of the gastrointestinal tract. Previously, we and others showed that the widely expressed transcription factor is expressed at higher protein levels in stem cells, including intestinal stem cells. In this study we use a conditional mouseOct1(Pou2f1) allele deleted in two different intestinal stem cell compartments. The results indicate that Oct1 loss is dispensable for maintenance of the mouse gut, but required for regeneration. We also tested Oct1 loss in the context of two different mouse colon cancer models. We find that Oct1 loss has opposing effects in the two models, and further that the two models are associated with different gene expression signatures. The differentially expressed genes are enriched for previously identified Oct1 targets, suggesting that differential gene control by Oct1 is one mechanism underlying different outcomes.

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