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RNA sequencing analysis of TNBC PDX treated with MLK3 and pan MLK's inhibitor

ABSTRACT: RNA sequencing analysis of TNBC PDX treated with MLK3 and pan MLK's inhibitor

PROVIDER: PRJNA780884 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16957249.fastq.gz	Fastqsanger.gz
	SRR16957250.fastq.gz	Fastqsanger.gz
	SRR16957251.fastq.gz	Fastqsanger.gz
	SRR16957252.fastq.gz	Fastqsanger.gz
	SRR16957253.fastq.gz	Fastqsanger.gz

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RNA sequencing analysis of TNBC PDX treated with MLK3 and pan MLK's inhibitor

Project description:Mixed Lineage Kinase 3 (MLK3) is a viable emerging target for neoplastic diseases; however, it is uncertain whether its activators or inhibitors can act as anti-neoplastic agents. Previously, we reported that the kinase activity of MLK3 was significantly higher in triple-negative breast cancer (TNBC) than hormone receptor-positive human breast tumors where estrogen inhibits MLK3 kinase activity and provides a survival advantage to ER+ breast cancer cells. Here, we identified that in TNBC, the higher MLK3 kinase activity paradoxically promotes cell survival via activating the downstream PAK1-NF-kB axis. The MLKs/MLK3 inhibitors, CEP-1347, and URMC-099 induced cell death in TNBC but not in hormone receptor-positive breast cancer cells. The MLKs/MLK3 inhibitors reduced TNBC cell line and patient-derived xenografts’ tumor burden. The MLKs/MLK3 inhibitors also decreased MLK3, PAK1, and NF-kB protein expression and activation, prompting cell death in breast PDXs. The RNA-seq analyses indicated several genes downregulated upon MLKs/MLK3 inhibition in tumors. Significantly NGF/TrkA MAPK pathway was enriched in tumors undergoing tumor reduction by CEP-1347 and URMC-099. The tumors or cell lines that did respond to MLKs/MLK3 inhibitors had higher TrkA expression, and TrkA overexpression in the presence of MLK3 sensitized the TNBC cell line that initially did not respond to MLKs/MLK3 inhibitors. These results suggest that the functions of MLK3 in cancer cells are dependent on downstream targets/signaling, and rationalized decision needs to be made before using its inhibitor in different breast cancer subtypes. Our data also highlight that MLK3 inhibitor warrants further investigation for treating TNBC.

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Transcriptomic profiling of triple-negative breast cancer (TNBC) patient-derived xenografts (PDX) sensitive and resistant to docetaxel.

Project description:SurePrint G3 Human Gene Expression Microarray v2 was used to obtain gene expression profiles of two different TNBC PDX models sensitive to docetaxel and in the docetaxel resistant TNBC PDX models derived from both initially sensitive.

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Analysis of MLK3-dependent gene expression in carcinogen-induced murine hepatocellular carcinoma

Project description:Hepatocellular carcinoma (HCC) is one of the most common gastrointestinal (GI) malignancies and a major cause of death worldwide, with limited therapeutic options. Although Mixed Lineage Kinase 3 (MLK3), a MAPKKK, has emerged as a key regulator of acute liver injury, inflammation, and non-alcoholic steatohepatitis (NASH), its role in HCC remains unclear. TCGA databases suggest an elevated expression of MAP3K11 (gene of MLK3) and TMA studies show higher MLK3 activation in human HCCs compared to the normal livers. We demonstrate here that MLK3 kinase activity is upregulated in Diethylnitrosamine/phenobarbital (DEN/PB)-induced HCC, and MLK3 deficiency (MLK3-/-) alleviates HCC progression. Histological and biochemical analyses reveal that MLK3-/- reduces DEN/PB induced cell proliferation in vivo and MLK3 inhibition by si/shRNA or pharmacological inhibitors reduces cell proliferation and colony formation in vitro. Interestingly, MLK3-/- does not impair DEN-induced liver injury phenotypes at the early stage. RNA-sequencing analysis shows that MLK3-/- modulates the gene signature of various biological pathways, including epithelial-mesenchymal transition (EMT), and reduces TGFβ1&2 expressions. HCC cells overexpressing MLK3 promote EMT, and induction of TGFβ, suggesting MLK3 to be an upstream regulator of TGFβ signaling. In addition, MLK3-/- significantly reduces the activated hepatic stellate cell (HSC) signature, which is increased in DEN/PB-Wild-Type livers. Further analysis suggested that MLK3 might promote a paracrine increase in TGFβ expression leading to pSmad2 induction and HSC activation. Our work thus shows that MLK3 promotes HCC proliferation, TGFβ expression, and HSC activation, implying that pharmacological inhibition of MLK3 may have a significant clinical impact on HCC progression.

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Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound. Global RNA expression in primary cells from two MCL patients treated with a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor for 8 hours

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Human TNBC Cells 48h Treatment with OTSSP167 MELK Inhibitor vs. DMSO Control

Project description:Microarray comparing TNBC cells treated for 48 hours with OTSSp167 MELK Inhibitor and control (DMSO) Two-condition arrays: MDA-MB-231 cells were treated with either 4.5nM OTSSP167 MELK Inhibitor or 0.045% DMSO for 48h. Two biological replicates, one per array, with a dye swap (technical replicate).

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RNA Sequencing Gene Expression Profiles in Wild-Type and MLK2 and MLK3 double knockout (MLK2-/-MLK3-/-) Mouse Lung Endothelial Cells Under Normoxic and Hypoxic Conditions

Project description:MLK2 and MLK3 are key regulators of angiogenesis, particularly under hypoxic conditions. To investigate the underlying mechanisms, we performed unbiased RNA sequencing on primary lung endothelial cells isolated from wild-type and MLK2 and MLK3 double knockout (MLK2-/-MLK3-/-) mice exposed to normoxia or hypoxia. Transcriptomic analysis revealed significant enrichment of the “Pathways in cancer” and “HIF1α signaling pathway,” which regulate proangiogenic genes. Our RNA Seq data suggest that, mechanistically, MLKs act through the long noncoding RNA H19 to regulate angiogenic gene expression. These findings identify the MLK-H19 axis as a critical regulator of endothelial function and a key driver of tumor-associated angiogenesis

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Human TNBC Cells 72h Treatment with 45nM OTSSP167 MELK Inhibitor vs. DMSO Control

Project description:Microarray comparing TNBC cells treated for 72 hours with OTSSP167 MELK Inhibitor and control (DMSO) Two-condition arrays: MDA-MB-231 cells were treated with either 45nM OTSSP167 MELK Inhibitor or 0.045% DMSO for 72h. Two biological replicates, one per array, with a dye swap (technical replicate).

2017-05-01 | E-GEOD-68692 | biostudies-arrayexpress

Human TNBC Cells 72h Treatment with 4.5nM OTSSP167 MELK Inhibitor vs. DMSO Control

Project description:Microarray comparing TNBC cells treated for 72 hours with OTSSP167 MELK Inhibitor and control (DMSO) Two-condition arrays: MDA-MB-231 cells were treated with either 4.5nM OTSSP167 MELK Inhibitor or 0.045% DMSO for 72h. Two biological replicates, one per array, with a dye swap (technical replicate).

2017-05-01 | E-GEOD-68691 | biostudies-arrayexpress

Human TNBC Cells 72h Treatment with 4.5nM OTSSP167 MELK Inhibitor vs. DMSO Control (SUM159)

Project description:Microarray comparing TNBC cells treated for 72 hours with OTSSP167 MELK Inhibitor and control (DMSO) Two-condition arrays: SUM159 cells were treated with either 4.5nM OTSSP167 MELK Inhibitor or 0.045% DMSO for 72h. Two biological replicates, one per array, with a dye swap (technical replicate).

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Project description:Microarray comparing TNBC cells treated for 72 hours with OTSSP167 MELK Inhibitor and control (DMSO) Two-condition arrays: SUM159 cells were treated with either 45nM OTSSP167 MELK Inhibitor or 0.045% DMSO for 72h. Two biological replicates, one per array, with a dye swap (technical replicate).

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