Combined MEK and JAK/STAT3 pathway inhibition effectively decreases medulloblastoma tumor progression.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE165960 | GEO | 2022/07/04
REPOSITORIES: GEO
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Project description:Combined MEK and JAK/STAT3 pathway inhibition effectively decreases medulloblastoma tumor progression.
| PRJNA698708 | ENA
Project description:Medulloblastoma (MB) is the most common primary malignant pediatric brain cancer. We recently identified novel roles for the MEK/MAPK pathway in regulating human Sonic Hedgehog (SHH) MB tumorigenesis. The MEK inhibitor, selumetinib, decreased SHH MB growth while extending survival in mouse models. However, the treated mice ultimately succumbed to disease progression. Here, we perform RNA sequencing on selumetinib-treated orthotopic xenografts to identify molecular pathways that compensate for MEK inhibition specifically in vivo. Notably, the JAK/STAT3 pathway exhibits increased activation in selumetinib-treated tumors. The combination of selumetinib and the JAK/STAT3 pathway inhibitor, pacritinib, further reduces growth in two xenograft models and also enhances survival. Multiplex spatial profiling of proteins in drug-treated xenografts reveals shifted molecular dependencies and compensatory changes following combination drug treatment. Our study warrants further investigation into MEK and JAK/STAT3 inhibition as a novel combinatory therapeutic strategy for SHH MB.
| S-EPMC9283517 | biostudies-literature
Project description:To identify downstream targets of Jak/Stat3 pathways without being distracted by differentiation signalings from MEK/ERK pathway, we exploited a engineered B6 cells, which stably stably expressing a chimeric receptor (GRgp-Y118F). The chimeric receptor can induce the phosphorylation of Stat3 by GCSF without activating the MEK/ERK pathway. To mimic the effect of GCSF, the chimeric B6 cells were also treated with LIF plus a selective MEK chemical inhibitor, PD0325901, to induce LIF/Jak/Stat3 but MEK/ERK pathways. mESCs starved in serum free growth medium for 6hrs were treated with GCSF or with LIF plus PD0325901 for 1hr, after which total RNA was extracted for analysis.
2012-06-13 | E-GEOD-38719 | biostudies-arrayexpress
Project description:Overactive RAS signaling is prevalent in juvenile myelomonocytic leukemia (JMML) and the myeloproliferative variant of chronic myelomonocytic leukemia (MP-CMML) in humans, and both are refractory to conventional chemotherapy. Conditional activation of a constitutively active oncogenic Nras (NrasG12D/G12D) in murine hematopoietic cells promotes an acute myeloproliferative neoplasm (MPN) that recapitulates many features of JMML and MP-CMML. We found that NrasG12D/G12D-expressing HSCs, which serve as JMML/MP-CMML-initiating cells, show strong hyperactivation of ERK1/2, promoting hyperproliferation and depletion of HSCs and expansion of downstream progenitors. Inhibition of the MEK pathway alone prolonged the presence of NrasG12D/G12D-expressing HSCs but failed to restore their proper function. Consequently, approximately 60% of NrasG12D/G12D mice treated with MEK inhibitor alone died within 20 weeks, and the remaining animals continued to display JMML/MP-CMML-like phenotypes. In contrast, combined inhibition of MEK and JAK/STAT signaling, which is commonly hyperactivated in human and mouse CMML, potently inhibited human and mouse CMML cell growth in vitro, rescued mutant NrasG12D/G12D-expressing HSC function in vivo, and promoted long-term survival without evident disease manifestation in NrasG12D/G12D animals. These results provide a strong rationale for further exploration of combined targeting of MEK/ERK and JAK/STAT in treating patients with JMML and MP-CMML.
| S-EPMC4038579 | biostudies-literature
Project description:We performed RNAseq analysis to dissect the dynamic transcriptome change during mouse iPSC induction, with or without blocking the Jak/Stat3 activity. We described Jak/Stat3 activity-specific global gene expression patterns, biological events, and regulation of key pluripotent genes, epigenetic modulators, and non-coding RNAs during the reprogramming process. We further demonstrated that Jak/Stat3 activity is essential for proper imprint of Dlk1-Dio3 region that is necessary for complete pluripotency establishment. Functional analysis revealed that one Jak/Stat3 downstream targets identified in our study - Esrrb significantly rescues reprogramming despite the inhibition of Jak/Stat3 activity. Our data illustrated novel mechanism in Jak/Stat3 promoted pluripotency establishment, which is valuable for further improvement of naïve-state iPSC generation across different species.
2017-08-18 | GSE97261 | GEO
Project description:To identify downstream targets of Jak/Stat3 pathways without being distracted by differentiation signalings from MEK/ERK pathway, we exploited a engineered B6 cells, which stably stably expressing a chimeric receptor (GRgp-Y118F). The chimeric receptor can induce the phosphorylation of Stat3 by GCSF without activating the MEK/ERK pathway. To mimic the effect of GCSF, the chimeric B6 cells were also treated with LIF plus a selective MEK chemical inhibitor, PD0325901, to induce LIF/Jak/Stat3 but MEK/ERK pathways.
2012-06-14 | GSE38719 | GEO
Project description:Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy. 8 female C57BL/6JTgMISIIR-TAg mice with ovarian tumors of ~500 mm3 were used. 4 vehicle-treated mice (0.5% hypermellose/0.1%Tween 80);4 drug-treated mice (30 mg/kg AZD1480 in 0.5% hypermellose/0.1%Tween 80).
2015-02-01 | E-GEOD-63092 | biostudies-arrayexpress
Project description:Chronic inflammation represents a major threat to human health since long-term systemic inflammation is known to affect distinct tissues and organs. Recently, solid evidence demonstrated that chronic inflammation affects hematopoiesis; however, how chronic inflammation affects hematopoietic stem cells (HSCs) on the mechanistic level is poorly understood. Here, we employ a mouse model of chronic multifocal osteomyelitis (CMO) to assess the effects of a spontaneously developed inflammatory condition on HSCs. We demonstrate that hematopoietic and nonhematopoietic compartments in CMO BM contribute to HSC expansion and impair their function. Remarkably, our results suggest that the typical features of murine multifocal osteomyelitis and the HSC phenotype are mechanistically decoupled. We show that the CMO environment imprints a myeloid gene signature and imposes a pro-inflammatory profile on HSCs. We identify IL-6 and the Jak/Stat3 signaling pathway as critical mediators. However, while IL-6 and Stat3 blockage reduce HSC numbers in CMO mice, only inhibition of Stat3 activity significantly rescues their fitness. Our data emphasize the detrimental effects of chronic inflammation on stem cell function, opening new venues for treatment.
| S-EPMC9827550 | biostudies-literature
Project description:There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) + SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo. Acquired resistance to the combination commonly resulted from the acquisition of TP53 mutations, conferring complete resistance to MDM2 inhibition. In contrast, resistant clones exhibited marked variability in sensitivity to MEK inhibition, which significantly impacted sensitivity to subsequent treatment with alternative MEK inhibitor-based combination therapies. These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and CRC.
2017-08-01 | GSE99015 | GEO
Project description:Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors, saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell cycle arrest in vitro and tumor inhibition in xenografts.
2018-03-28 | GSE112371 | GEO