References of "Cancer Research"
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See detailHemap: An nteractive online resource for characterizing molecular phenotypes across hematologic malignancies
Pölönen, Petri; Mehtonen, Juha; Lin, Jake et al

in Cancer Research (2019)

Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease contexts for new ... [more ▼]

Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease contexts for new therapeutic approaches. We analyzed 9,544 transcriptomes from over 30 hematologic malignancies, normal blood cell types and cell lines, and show that the disease types can be stratified in a data-driven manner. We utilized the obtained molecular clustering for discovery of cluster-specific pathway activity, new biomarkers and in silico drug target prioritization through integration with drug target databases. Using known vulnerabilities and available drug screens in benchmarking, we highlight the importance of integrating the molecular phenotype context and drug target expression for in silico prediction of drug responsiveness. Our analysis implicates BCL2 expression level as important indicator of venetoclax responsiveness and provides a rationale for its targeting in specific leukemia subtypes and multiple myeloma, links several polycomb group proteins that could be targeted by small molecules (SFMBT1, CBX7 and EZH1) with CLL, and supports CDK6 as disease-specific target in AML. Through integration with proteomics data, we characterized target protein expression for pre-B leukemia immunotherapy candidates, including DPEP1. These molecular data can be explored using our freely available interactive resource, Hemap, for expediting therapeutic innovations in hematologic malignancies. [less ▲]

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See detailThe microRNA-371~373 cluster represses colon cancer initiation and metastatic colonization by inhibiting the TGFBR2/ID1 signaling axis.
Ullmann, Pit UL; Rodriguez, Fabien UL; Schmitz, Martine UL et al

in Cancer research (2018)

The vast majority of colorectal cancer (CRC)-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key ... [more ▼]

The vast majority of colorectal cancer (CRC)-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different CRC cell lines and recently established primary cultures enriched in colon cancer stem cells (CSCs) - also known as tumor-initiating cells (TICs) - to identify genes and microRNAs (miRNAs) with regulatory functions in CRC progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, transforming growth factor beta (TGF-beta) signaling activity, and reduced expression of the miR-371~373 cluster compared to non-metastatic cultures. TGF-beta receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371~373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371~373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor-initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371~373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371~373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371~373 and ID1. Altogether, our results establish the miR-371~373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization. [less ▲]

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See detailDownregulation of the TGF-beta pseudoreceptor BAMBI in non-small cell lung cancer enhances TGF-beta signaling and invasion.
Marwitz, Sebastian; Depner, Sofia; Dvornikov, Dmytro et al

in Cancer research (2016)

Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where ... [more ▼]

Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where curative therapeutic options are lacking. In this study, we identify a targetable mechanism involving TGF-beta elevation that orchestrates tumor progression in this disease. Substantial activation of this pathway was detected in human lung cancer tissues with concomitant downregulation of BAMBI, a negative regulator of the TGF-beta signaling pathway. Alterations of epithelial-to-mesenchymal transition (EMT) marker expression were observed in lung cancer samples compared to tumor-free tissues. Distinct alterations in the DNA methylation of the gene regions encoding TGF-beta pathway components were detected in NSCLC samples compared to tumor-free lung tissues. In particular, epigenetic silencing of BAMBI was identified as a hallmark of NSCLC. Reconstitution of BAMBI expression in NSCLC cells resulted in a marked reduction of TGF-beta-induced EMT, migration and invasion in vitro, along with reduced tumor burden and tumor growth in vivo. In conclusion, our results demonstrate how BAMBI downregulation drives the invasiveness of NSCLC, highlighting TGF-beta signaling as a candidate therapeutic target in this setting. [less ▲]

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See detailSignatures of MicroRNAs and selected MicroRNA target genes in human melanoma
Philippidou, Demetra UL; Schmitt, Martina UL; Moser, Dirk et al

in Cancer Research (2010), 70(10), 4163-4173

Small noncoding microRNAs (miRNA) regulate the expression of target mRNAs by repressing their translation or orchestrating their sequence-specific degradation. In this study, we investigated miRNA and ... [more ▼]

Small noncoding microRNAs (miRNA) regulate the expression of target mRNAs by repressing their translation or orchestrating their sequence-specific degradation. In this study, we investigated miRNA and miRNA target gene expression patterns in melanoma to identify candidate biomarkers for early and progressive disease. Because data presently available on miRNA expression in melanoma are inconsistent thus far, we applied several different miRNA detection and profiling techniques on a panel of 10 cell lines and 20 patient samples representing nevi and primary or metastatic melanoma. Expression of selected miRNAs was inconsistent when comparing cell line-derived and patient-derived data. Moreover, as expected, some discrepancies were also detected when miRNA microarray data were correlated with qPCR-measured expression levels. Nevertheless, we identified miRNA-200c to be consistently downregulated in melanocytes, melanoma cell lines, and patient samples, whereas miRNA-205 and miRNA-23b were markedly reduced only in patient samples. In contrast, miR-146a and miR-155 were upregulated in all analyzed patients but none of the cell lines. Whole-genome microarrays were performed for analysis of selected melanoma cell lines to identify potential transcriptionally regulated miRNA target genes. Using Ingenuity pathway analysis, we identified a deregulated gene network centered around microphthalmia-associated transcription factor, a transcription factor known to play a key role in melanoma development. Our findings define miRNAs and miRNA target genes that offer candidate biomarkers in human melanoma. ©2010 AACR. [less ▲]

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See detailIndibulin, a Novel Microtubule Inhibitor, Discriminates between Mature Neuronal and Nonneuronal Tubulin
Wienecke, Anke UL; Bacher, Gerald

in Cancer Research (2009), 69(1), 171-177

Microtubule inhibitors interfere with microtubule dynamics, causing cell cycle arrest and apoptosis. These effects are responsible for the chemotherapeutic activities of members of the taxane and Vinca ... [more ▼]

Microtubule inhibitors interfere with microtubule dynamics, causing cell cycle arrest and apoptosis. These effects are responsible for the chemotherapeutic activities of members of the taxane and Vinca alkaloid families in oncology. Unfortu- nately, a major side effect of the taxanes and Vinca alkaloids is the development of peripheral neuropathies. Indibulin (N-[pyridin-4-yl]-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid; D-24851; ZIO-301), a novel synthetic small molecule microtu- bule inhibitor, destabilizes microtubules and has antitumor activity but does not exhibit neurotoxicity in preclinical animal studies. In the present study, it has been found that indibulin is able to discriminate between highly posttranslationally modified tubulin present in mature neuronal micro- tubules, and less-modified tubulin present in immature neuronal or nonneuronal microtubules. Vincristine and colchicine act on either tubulin equally well. The binding site of indibulin on mature neuronal microtubules seems to be inaccessible due to the posttranslational modifications, a theory that is supported by the observation that indibulin did not disrupt the integrity of highly modified microtubules present in neurites of pheochromocytoma (PC12) cells. The specificity of indibulin for unmodified microtubules seems to be dependent on the pyridyl moiety of indibulin because derivatives that have the pyridyl moiety replaced are not able to discriminate between highly and less-modified tubulins. The observed broad antitumor activity of indibulin and the lack of central and peripheral nervous system toxicity in preclinical studies make it a promising candidate for development as a cancer treatment. Indibulin is currently in phase I clinical trials. [less ▲]

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