Endothelial Shp2 deficiency controls alternative activation of macrophage preventing radiation-induced lung injury through Notch signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA789539 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17248219_1.fastq.gz | Fastqsanger.gz | |||
| SRR17248219_2.fastq.gz | Fastqsanger.gz | |||
| SRR17248220_1.fastq.gz | Fastqsanger.gz | |||
| SRR17248220_2.fastq.gz | Fastqsanger.gz | |||
| SRR17248221_1.fastq.gz | Fastqsanger.gz |
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Project description:Radiation-induced lung injury is a common late side-effect of thoracic radiotherapy. The inflammatory microenvironment plays a key role in this process. Endothelial cells are the goalkeeper of inflammation. Endothelial dysfunction following leukocytes infiltrated is a prominent feature in the pathogenesis of radiation-induced lung injury. Tyrosine phosphatase Shp2 is a key regulator of endothelial functions and inflammation. Here, we established a clinical-mimicking mouse model of radiation-induced lung injury and found that Shp2 activity was elevated in endothelium after injury. Mice with endothelium-specific Shp2 deletion showed relieved collagen deposition along with disrupted radiation-induced Jag1 expression in the endothelium. Furthermore, endothelium-derived Jag1 activated the alternative activation of macrophages in vitro and in vivo by paracrine Notch signaling. Consistently, Notch pathway was significant activated by chest irradiation in the peripheral blood leukocytes of cancer patients. Collectively, this is the first demonstration of radiation-induced lung injury regulation by endothelial Shp2. Shp2 participates in the radiation-induced endothelial dysfunction and subsequently inflammatory microenvironment producing.
2021-12-18 | GSE191056 | GEO
Project description:In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated ?-gal (SA-?-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, Focal adhesion kinase and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies which rely on senescence induction by inhibiting Shp2 or controlling its target gene products may be useful in blocking breast cancer. Primary mammary tumor cells from MMTV-PyMT mice were cultured as mammospheres for 10 days and then treated with specific inhibitors of Notch (DAPT), MEK1 (U0126), FAK (TAE226), or Src (PP2) for another 2 days. Mammospheres were then subjected to RNA isolation. Each group contains 3 replicates.
2015-03-06 | E-GEOD-50517 | biostudies-arrayexpress
Project description:The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases (RTKs), as it is required for full RAS-ERK activation to promote cell proliferation and survival programs. SHP2 allosteric inhibitors act by stabilizing SHP2 in its auto-inhibited conformation and they are currently being tested in clinical trials for tumors with over-activation of the RAS/ERK pathway, alone and in various drug combinations. Using in vitro models, we established acquired resistant cell lines to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD-positive AML cell lines. We performed both label-free and isobaric labeling quantitative mass spectrometry-based phosphoproteomics to reveal that AML cells can restore phosphorylated ERK (pERK) in presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induces the tyrosine phosphorylation and feedback-activation of the FLT3 receptor, which in turn phosphorylates SHP2 on Tyrosine 62. This phosphorylation stabilizes SHP2 in its open conformation, preventing SHP099 binding, thus resulting in resistance. Combinatorial inhibition of SHP2 and MEK or SHP2 and FLT3 prevents pERK rebound and resistant cell growth. We observed the same mechanism in a FLT3-mutated B-ALL cell line and in the inv(16)/KITD816Y AML mouse model. Finally, we show that allosteric SHP2 inhibition does not impair the clonogenic ability of normal bone marrow progenitors, supporting its future use for clinical applications.
2023-03-10 | PXD030338 | Pride
Project description:In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, Focal adhesion kinase and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies which rely on senescence induction by inhibiting Shp2 or controlling its target gene products may be useful in blocking breast cancer. For Shp2 ablation, primary mammary tumor cells from MMTV-PyMT;Shp2fl/fl mice were transduced with retroviruses expressing control GFP or CreERT2-GFP, and GFP-positive cells were purified by FACS and cultured as mammospheres for 1 week. Mammospheres were then treated with 50 nM 4-OHT for 2 hours, cultured for another 5 days, and subjected to RNA isolation. For pharmacological inhibition, primary mammary tumor cells from the same mice were cultured as mammospheres for 10 days and then treated with the Shp2 inhibitor GS493 for another 2 days. Mammospheres were then subjected to RNA isolation. Each group contains 3 replicates.
2015-03-06 | E-GEOD-50516 | biostudies-arrayexpress
Project description:1205Lu Metastatic Human melanoma cell lines with knockdown of Shp2 (PTPN11) were grown as xenograft tumors in NSG mice. RNA was extracted from the tumors and analyzed on [HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array [transcript (gene) version] Shp2 knockdown compared with non-target controls
2016-07-03 | E-GEOD-53282 | biostudies-arrayexpress
Project description:In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, Focal adhesion kinase and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies which rely on senescence induction by inhibiting Shp2 or controlling its target gene products may be useful in blocking breast cancer.
2015-03-06 | GSE50516 | GEO
Project description:In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, Focal adhesion kinase and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies which rely on senescence induction by inhibiting Shp2 or controlling its target gene products may be useful in blocking breast cancer.
2015-03-06 | GSE50517 | GEO
Project description:The first bona fide PTP proto-oncogene was the Src-homology 2 domain-containing phosphatase SHP2 (encoded by PTPN11), an ubiquitously expressed PTP that transduces mitogenic, pro-survival, cell fate and/or pro-migratory signals from numerous growth factor-, cytokine- and extracellular matrix receptors. In malignancies, SHP2 is hyperactivated either downstream of oncoproteins or by mutations.We provide analysis of the breast cancer cells BT474 grown as xenografts in the presence or absence of SHP2 for 30 days. The HER2-postive breast cancer cell line BT474 was transduced with a doxycycline-inducible lentiviral vector expressing a CTRL miR or SHP2 miR1 or SHP2 miR2. Cells from each group were injected in imuunodeficinet mice and after tumor development, the knockdown of SHP2 was induced for 30 days in vivo. At day 30, tumors were dissected and RNA isolated for gene expression analysis.
2011-12-20 | E-GEOD-34523 | biostudies-arrayexpress
Project description:The first bona fide PTP proto-oncogene was the Src-homology 2 domain-containing phosphatase SHP2 (encoded by PTPN11), an ubiquitously expressed PTP that transduces mitogenic, pro-survival, cell fate and/or pro-migratory signals from numerous growth factor-, cytokine- and extracellular matrix receptors. In malignancies, SHP2 is hyperactivated either downstream of oncoproteins or by mutations.We provide analysis of a primary triple-negative breast tumor grown as xenografts in the presence or absence of SHP2 for 30 days. A primary triple-negative breast tumor (BT8) was transduced with a doxycycline-inducible lentiviral vector expressing a CTRL miR or SHP2 miR1 or SHP2 miR2. Cells from each group were injected in immunodeficient mice and after tumor development, the knockdown of SHP2 was induced for 30 days in vivo. At day 30, tumors were dissected and RNA isolated for gene expression analysis.
2012-01-16 | E-GEOD-35118 | biostudies-arrayexpress
Project description:Radiotherapy, a treatment modality received by more than half of all cancer patients, remains one of the most effective approaches to achieve local tumour control. Despite increased accuracy driven by technological advances, healthy tissue injury due to off-target radiation exposure can still occur. In this study, we sought to understand the biological effect of radiation-mediated injury to the lung in the context of cancer metastasis, since we had previously reported that tissue regeneration is a feature of the metastatic microenvironment of this organ. We have exposed healthy mouse lung tissue to radiation prior to the induction of metastasis and observed a strong enhancement of cancer cell growth. Lung tissue was preconditioned into a profoundly tumour-supportive microenvironment governed by enhanced regenerative Notch signalling. Most importantly, we found that locally activated neutrophils were key drivers of these tissue perturbations, significantly increasing the metastatic proficiency of irradiated lung tissue and endowing arriving cancer cells with an augmented stemness phenotype. We show that by preventing neutrophil-dependent Notch activation in the irradiated tissue, we were able to significantly offset the radiation-enhanced metastases. Mechanistically, we identified the release of neutrophil granules as the effectors of the pro-tumorigenic preconditioning of the irradiated lung tissue. These findings not only reveal a novel tumour-supportive function of neutrophils in the context of tissue-injury, but also have important clinical implications by suggesting targeting their activity could maximise the success of radiotherapy for the treatment of cancer.
2021-12-13 | PXD027628 | Pride