Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA115597 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Tumor cells that give rise to metastatic disease are a primary cause of cancer-related death and have not been fully elucidated in patients with lung cancer. Here, we addressed this question by using tissues from a mouse that develops metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. We identified a metastasis-prone population of tumor cells that differed from those with low metastatic capacity on the basis of having sphere-forming capacity in Matrigel cultures, increased expression of CD133 and Notch ligands, and relatively low tumorigenicity in syngeneic mice. Knockdown of jagged1 or pharmacologic inhibition of its downstream mediator phosphatidylinositol 3-kinase abrogated the metastatic but not the tumorigenic activity of these cells. We conclude from these studies on a mouse model of lung adenocarcinoma that CD133 and Notch ligands mark a population of metastasis-prone tumor cells and that the efficacy of Notch inhibitors in metastasis prevention should be explored. Keywords: two group comparison 344SQ subcutaneous tumors (from a lung adenocarcinoma cell line derived from a KrasLA1/+; p53R172HdelG/+ mouse that metastasizes widely following subcutaneous injection into syngeneic mice) were sorted by flow cytometry into CD133high and CD133low fractions. RNA samples from these fractions were processed and analyzed on Affymetrix Mouse Expression Array 430A 2.0 chips.
2011-02-24 | E-GEOD-15587 | biostudies-arrayexpress
Project description:Tumor cells that give rise to metastatic disease are a primary cause of cancer-related death and have not been fully elucidated in patients with lung cancer. Here, we addressed this question by using tissues from a mouse that develops metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. We identified a metastasis-prone population of tumor cells that differed from those with low metastatic capacity on the basis of having sphere-forming capacity in Matrigel cultures, increased expression of CD133 and Notch ligands, and relatively low tumorigenicity in syngeneic mice. Knockdown of jagged1 or pharmacologic inhibition of its downstream mediator phosphatidylinositol 3-kinase abrogated the metastatic but not the tumorigenic activity of these cells. We conclude from these studies on a mouse model of lung adenocarcinoma that CD133 and Notch ligands mark a population of metastasis-prone tumor cells and that the efficacy of Notch inhibitors in metastasis prevention should be explored. Keywords: two group comparison
2011-02-24 | GSE15587 | GEO
Project description:Cell migration driven by actomyosin filament assembly is a critical step in tumour invasion and metastasis. Herein, we report identification of myosin binding protein H (MYBPH) as a transcriptional target of NKX2-1 (also known as TTF-1 and TITF1), a lineage-survival oncogene in lung adenocarcinoma. MYBPH inhibits assembly competence-conferring phosphorylation of the myosin regulatory light chain (RLC) as well as activating phosphorylation of LIM domain kinase (LIMK). These are unexpectedly implemented through direct physical interaction of MYBPH with Rho kinase 1 (ROCK1) rather than with RLC. In addition, MYBPH is shown to directly bind with non-muscle myosin heavy chain IIA (NMHC IIA), resulting in inhibition of NMHC IIA assembly. Thus, MYBPH plays multi-facetted roles in negative regulation of actomyosin organization, which in turn reduces cell motility, invasion, and metastasis. Finally, we also show that MYBPH is epigenetically inactivated by promoter DNA methylation in a fraction of lung adenocarcinomas abundantly expressing NKX2-1, which appears to be in accordance with its deleterious function for lung adenocarcinoma invasion and metastasis, as well as with the paradoxical association of NKX2-1 expression with favourable prognosis in lung adenocarcinoma patients. Dye-swap experiment, vector control vs. transiently transfectanted with TTF-1 in HPL1D, immortalized human peripheral lung epithelial cell line.
2011-12-22 | E-GEOD-26721 | biostudies-arrayexpress
Project description:We have identified the histone methyltransferases G9a/Glp as suppressors of aggressive lung tumor-propagating cells (TPCs). Chemically inhibiting G9a/Glp promoted TPC phenotypes in lung adenocarcinoma cells, and caused chromatin changes at genes associated with the differentiation of stem cells. G9a/Glp inhibition in lung progenitor cell organoid cultures disrupted alveolar differentiation. Depleting G9a during tumorigenesis enriched for TPCs, accelerating disease progression and metastasis. Demethylase inhibition decreased lung adenocarcinoma progression in vivo.
2018-11-30 | GSE100455 | GEO
Project description:We have identified the histone methyltransferases G9a/Glp as suppressors of aggressive lung tumor-propagating cells (TPCs). Chemically inhibiting G9a/Glp promoted TPC phenotypes in lung adenocarcinoma cells, and caused chromatin changes at genes associated with the differentiation of stem cells. G9a/Glp inhibition in lung progenitor cell organoid cultures disrupted alveolar differentiation. Depleting G9a during tumorigenesis enriched for TPCs, accelerating disease progression and metastasis. Demethylase inhibition decreased lung adenocarcinoma progression in vivo.
2021-04-19 | GSE113402 | GEO
Project description:Cell migration driven by actomyosin filament assembly is a critical step in tumour invasion and metastasis. Herein, we report identification of myosin binding protein H (MYBPH) as a transcriptional target of NKX2-1 (also known as TTF-1 and TITF1), a lineage-survival oncogene in lung adenocarcinoma. MYBPH inhibits assembly competence-conferring phosphorylation of the myosin regulatory light chain (RLC) as well as activating phosphorylation of LIM domain kinase (LIMK). These are unexpectedly implemented through direct physical interaction of MYBPH with Rho kinase 1 (ROCK1) rather than with RLC. In addition, MYBPH is shown to directly bind with non-muscle myosin heavy chain IIA (NMHC IIA), resulting in inhibition of NMHC IIA assembly. Thus, MYBPH plays multi-facetted roles in negative regulation of actomyosin organization, which in turn reduces cell motility, invasion, and metastasis. Finally, we also show that MYBPH is epigenetically inactivated by promoter DNA methylation in a fraction of lung adenocarcinomas abundantly expressing NKX2-1, which appears to be in accordance with its deleterious function for lung adenocarcinoma invasion and metastasis, as well as with the paradoxical association of NKX2-1 expression with favourable prognosis in lung adenocarcinoma patients.
2011-12-22 | GSE26721 | GEO
Project description:Sustained tumor progression has been attributed to a distinct population of tumor-propagating cells (TPCs). To identify TPCs relevant to lung cancer pathogenesis, we investigated functional heterogeneity in tumor cells isolated from Kras-driven mouse models of non-small cell lung cancer (NSCLC). CD24+ITGB4+Notchhi cells are capable of propagating tumor growth in both a clonogenic and an orthotopic serial transplantation assay. While all four Notch receptors mark TPCs, Notch3 plays a non-redundant role in tumor cell propagation in two mouse model and in human NSCLC. The TPC population is enriched after chemotherapy and the gene signature of mouse TPCs correlates with poor prognosis in human NSCLC. The unique role of Notch3 in tumor propagation may provide a therapeutic target for NSCLC Primary lung adenocarcinoma tumor cells were FACS sorted based on expression of CD24, ITGB4 and Notch. TPC cells are defined by Cd24+ITGB4+ Notch(high), and the remainder tumor cells are non-TPC cells. Samples were derived from six mice.
2013-07-08 | E-GEOD-46439 | biostudies-arrayexpress
Project description:Lung cancer is the leading cause of cancer death worldwide. Brain metastasis is a major cause of morbidity and mortality in lung cancer. CDH2 (N-cadherin, a mesenchymal marker in epithelial-mesenchymal transition) and ADAM9 (a member of type I transmembrane proteins) have been reported relating to lung cancer brain metastasis, however, it is still not clear whether any interaction between them to mediate lung cancer brain metastasis. Since microRNAs were discovered to regulate many biological functions and disease processes (e.g., cancer) by down-regulating their target genes, microRNA microarrays were used to identify ADAM9 regulated miRNAs that target CDH2 in aggressive lung cancer cells. Luciferase assays and immunoblotting proved that CDH2 was a target gene of miR-218. The expression of miR-218 was generated from pri-mir-218-1, located in SLIT2, in low invasive lung adenocarcinoma while it was inhibited in aggressive lung adenocarcinoma. Down-regulation of ADAM9 could up-regulate SLIT2 and miR-218, thus down-regulate CDH2 expression. This study elucidated the mechanism of ADAM9 activating CDH2 may be due to release the inhibition of miR-218 on CDH2 in lung adenocarcinoma. For each of the cell lines bm#2, bm#7, and F4, one microarray was analyzed.
2016-07-03 | E-GEOD-52050 | biostudies-arrayexpress
Project description:Lung cancer is the leading cause of cancer death worldwide. Brain metastasis is a major cause of morbidity and mortality in lung cancer. CDH2 (N-cadherin, a mesenchymal marker in epithelial-mesenchymal transition) and ADAM9 (a member of type I transmembrane proteins) have been reported relating to lung cancer brain metastasis, however, it is still not clear whether any interaction between them to mediate lung cancer brain metastasis. Since microRNAs were discovered to regulate many biological functions and disease processes (e.g., cancer) by down-regulating their target genes, microRNA microarrays were used to identify ADAM9 regulated miRNAs that target CDH2 in aggressive lung cancer cells. Luciferase assays and immunoblotting proved that CDH2 was a target gene of miR-218. The expression of miR-218 was generated from pri-mir-218-1, located in SLIT2, in low invasive lung adenocarcinoma while it was inhibited in aggressive lung adenocarcinoma. Down-regulation of ADAM9 could up-regulate SLIT2 and miR-218, thus down-regulate CDH2 expression. This study elucidated the mechanism of ADAM9 activating CDH2 may be due to release the inhibition of miR-218 on CDH2 in lung adenocarcinoma. For each of the cell lines bm#2, bm#7, and F4, one microarray was analyzed.
2016-07-03 | E-GEOD-51833 | biostudies-arrayexpress
Project description:Mutations in the epidermal growth factor receptor (EGFR) kinase domain occur in 10-30% of lung adenocarcinoma. Leucine to arginine substitution at amino acid position 858 (L858R) accounts for around 50% of EGFR-tyrosine kinase inhibitor (TKI) sensitizing mutations. A second site mutation in the gatekeeper residue (T790M) accounts for around 60% of acquired resistance to EGFR-TKIs. We sought to identify the immediate direct and indirect targets of these mutant EGFRs in lung adenocarcinoma and their modulation by erlotinib, the first generation, and most widely used EGFR-directed TKI. We undertook stable isotope labeling of amino acids in cell culture (SILAC), phosphopeptide enrichment, and quantitative mass spectrometry to identify dynamic changes of phosphorylation downstream of mutant EGFRs in lung adenocarcinoma cells harboring L858R or L858R/T790M mutations and their modulation by erlotinib inhibition. Phosphorylation at the majority of phosphosites identified exhibited no change upon either EGF stimulation or erlotinib inhibition. Only around 7% of phosphosites identified and quantified showed increased phosphorylation upon EGF stimulation in either cell line. However, while phosphorylation at 61% of these phosphosites decreased upon erlotinib inhibition in the TKI sensitive H3255 cells, only 24% of such sites exhibited decreased phosphorylation upon erlotinib inhibition in the TKI resistant H1975 cells. Top canonical pathways that were inhibited upon erlotinib treatment in sensitive cells, but not the resistant cells include EGFR, Insulin receptor, HGF, MAPK, mTOR, p70S6K and JAK/STAT signaling. We identified phosphosites in proteins of the autophagy network, such as ULK1 (S623) that is constitutive phosphorylated in these lung adenocarcinoma cells, but phosphorylation is inhibited upon erlotinib treatment in sensitive cells, but not resistant cells. Finally, kinase-substrate prediction analysis from our data indicated that substrates of basophilic kinase families, AGC, CAMK and STE were significantly enriched and those of proline directed kinase families, CMGC and CK were significantly depleted among substrates that exhibit increased phosphorylation upon EGF stimulation and reduced phosphorylation upon TKI inhibition. This is the first study to date to examine global phosphorylation changes upon erlotinib treatment of lung adenocarcinoma cells and results from this study provide new insights into signaling downstream of mutant EGFRs in lung adenocarcinoma.
2015-01-30 | PXD001101 | Pride