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Gene expression profiling of metastatic lung cancer cell lines

ABSTRACT: During malignant disease progression, the extracellular matrix (ECM) of epithelial tumors accumulates inter-molecular cross-links between collagen strands; these cross-links enhance ECM stiffness and trigger tumor cell invasion and dissemination, but the mechanisms that regulate intra-tumoral collagen maturation have not been fully defined. Using a new mouse model of metastatic lung adenocarcinoma driven by mutant K-ras expression and Cdkn1a inactivation, we showed that tumor cell invasion and metastasis are driven by high expression of lysyl hydroxylase 2 (LH2), an enzyme that hydroxylates telomeric lysine (Lys) residues on collagen.

ORGANISM(S): Mus musculus

PROVIDER: GSE49315 | GEO | 2015/03/12

SECONDARY ACCESSION(S): PRJNA213622

REPOSITORIES: GEO

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Gene expression profiling of metastatic lung cancer cell lines

Project description:During malignant disease progression, the extracellular matrix (ECM) of epithelial tumors accumulates inter-molecular cross-links between collagen strands; these cross-links enhance ECM stiffness and trigger tumor cell invasion and dissemination, but the mechanisms that regulate intra-tumoral collagen maturation have not been fully defined. Using a new mouse model of metastatic lung adenocarcinoma driven by mutant K-ras expression and Cdkn1a inactivation, we showed that tumor cell invasion and metastasis are driven by high expression of lysyl hydroxylase 2 (LH2), an enzyme that hydroxylates telomeric lysine (Lys) residues on collagen. We interbred KrasLA1 mice, which develop non-metastatic lung adenocarcinomas at 8-10 months of age because of the expression of a somatically activated K-rasG12D allele, with Cdkn1a-/- mice, which develop sarcomas and B cell lymphomas because of depletion of p21. Cohorts were generated that had neither, either, or both mutant alleles. KrasLA1 mice that were p21-deficient (KC mice) had a shorter mean time to death than did p21-replete ones. We established cell lines from the tumors, and compared cell lines from highly metastatic tumors with those from poorly metastatic tumors.

2015-03-12 | E-GEOD-49315 | biostudies-arrayexpress

Lysyl hydroxylase 1 deficiency exacerbates the alterations of gene transcriptional profile of abdominal aorta in angiotensin II induced abdominal aortic aneurysm

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Cardiac Outflow tract septation defects in a DiGeorge syndrome model respond to Minoxidil treatment

Project description:We found that Tbx1 suppresses a subset of ECM-related genes in a cell differentiation model. Treatment with a Lysyl hydroxylase inhibitor drug in vivo during pregnancy reduced the expressivity of cardiac defects in Tbx1 mutant embryos.

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Lysyl hydroxylase 2 deficiency promotes filopodia formation and fibroblast migration

Project description:Lysyl hydroxylase 2 (LH2) regulates the intermolecular cross-linking of collagen molecules. Accumulation of LH2-modified collagen, which is highly stable and resistant to collagenase cleavage, is one of the causes of fibrosis. In this study, we established LH2-deficient fibroblasts and first analyzed morphology of LH2-deficient fibroblasts by microscopy. LH2-deficient fibroblasts showed a dramatic increase in filopodial dynamics and cell migration, which were supported by time-lapse video microscopy and Immunocytochemistry, and gene expression profiling data. Understanding the precise role of phenotype in LH2-deficient cells may be helpful to define the pathogenesis of fibrosis.

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2022-10-05 | PXD036736 | Pride

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Gene array data from LOX p0 Mouse pups

Project description:Lysyl oxidase is an extracellular enzyme essential for crosslinking elastin and collagen. Mice that do not express Lox have 60% and 40% reductions in elastin-specific and collagen-specific crosslinks, respectively. Mutations in LOX are associated with thoracic aortic aneurysm and dissection (TAAD). Lysyl oxidase knockout mice dye perinatally with ruptured diaphragm, tortuous arteries, and TAAD This is the first study to analyze the mechanical and genetic changes induced by the absence of lysyl oxidase in the thoracic aorta, and may provide new therapeutic targets relevant for the pathogenesis of thoracic aortic aneurysms and dissections

2016-10-28 | GSE89227 | GEO

Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2

Project description:Matrix stiffening by lysyl oxidase-like 2 (LOXL2) mediated collagen cross-linking is proposed as a core feed-forward mechanism that promotes fibrogenesis. Failure in clinical trials of simtuzumab (the humanized version of AB0023, a monoclonal antibody against human LOXL2) suggested targeting LOXL2 may not have disease relevance, however target engagement was not directly evaluated. We compared the spatial transcriptome of active human lung fibrogenesis sites with different human cell culture models to determine the model with greatest disease relevance. Within the selected model system, we then evaluated AB0023, identifying that it did not inhibit collagen cross-linking or reduce tissue stiffness, nor did it inhibit LOXL2 catalytic activity. In contrast it did potently inhibit angiogenesis consistent with an alternative, non-enzymatic mechanism of action. Thus, AB0023 is anti-angiogenic but does not inhibit LOXL2 catalytic activity, collagen cross-linking or tissue stiffening. These findings have implications for the interpretation of lack of efficacy of simtuzumab in clinical trials of fibrotic diseases.

2024-02-19 | GSE255705 | GEO

Cross-linking mass spectrometry analyses of three different kinetochore protein complexes (KMN, NDC80C, MIS12C) using an MS-cleavable cross-linker, BuUrBu (DSBU)

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