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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

Project description:Lysyl hydroxylase 1 (LH1) plays an important role in hydroxylation of lysyl residuel in Xaa-Lys-Gly. The hydroxylysine residues serve as sites of attachment for carbohydrate units which are essential for the formation of intra- and intermolecular collagen crosslinks. To gain mechanistic insights into the effects of LH1 deficiency on abdominal aortic aneurysm (AAA) formation, a whole transcriptomic analysis of abdominal aorta were performed using RNA-seq. The abdominal aorta of mice for RNA-seq were acquired at day 14 after angiotensin II infusion in order to provide the mechanistic or causal evidence of a direct participatory role of LH1 to the effects of AAA.

2021-08-15 | GSE175683 | GEO

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.

2021-10-20 | GSE186100 | GEO

Lysyl hydroxylase 3 mediated post-translational modifications are required for proper biosynthesis of collagen a1a1a2(IV)

Project description:We performed proteomic identification of type IV collagen gel bands from wild-type and lysyl hydroxylase 3 knockout cells by LC-MS after trypsin digestion.

2022-11-21 | PXD035051 | JPOST Repository

Characterization of Chemotherapy-treated PyMT Liver Matrisome

Project description:Metastasis accounts for 90% of cancer-related deaths, yet the mechanisms by which cancer cells colonize secondary organs remain poorly understood. For breast cancer patients, metastasis to the liver is associated with poor prognosis and a median survival of 6 months. Standard of care is chemotherapy, but recurrence occurs in 30% of patients. Systemic chemotherapy has been shown to induce hepatotoxicity and fibrosis, but how chemotherapy impacts the composition of the liver extracellular matrix (ECM) remains unknown. Individual ECM proteins drive tumor cell proliferation and invasion, features that are essential for metastatic outgrowth in the liver. Here, we characterize the liver ECM of tumor-bearing mice treated with and without chemotherapy using the MMTV-PyMT transgenic model of breast cancer. We identify distinct drug-specific changes induced by commonly used cytotoxic chemotherapies. We identify Collagen V as an ECM protein that is more abundant in livers isolated from paclitaxel-treated mice and identify mechanisms of Collagen V driven invasion via ECM organization and signaling through α1β1 integrins.

2022-10-05 | PXD036736 | Pride

A First-in-Class Pan-Lysyl Oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

Project description:The lysyl oxidase family represents a promising target in stromal targeting of solid tumours due to the importance of this family in cross-linking and stabilising fibrillar collagens, and its known role in tumour desmoplasia. Using small-molecule drug design approaches, we generated and validated PXS-5505, a first-in-class, highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumour desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumour perfusion, and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, whilst also demonstrating anti-fibrotic effects in human PDX models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of the first pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.

2023-05-18 | GSE186748 | GEO

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)

Project description:In order to develop a simplified cross-linking mass spectrometry protocol, we applied one-step size-exclusion chromatography (SEC) for peptide purification after proteolysis with Lys-C and trypsin. Three benchmark protein complexes (KMN, NDC80C, MIS12C) from human kinetochore were cross-linked with an MS-cleavable cross-linker (BuUrBu). After proteolysis, digested peptides were purified with SEC omitting the step of C18 column to avoid loss of cross-linked peptides. Our protocol showed improvement of existing protocols, and we could successfully identify over 700 cross-links per experiment of each of the three protein complexes. We also observed that about half of the non-redundant cross-links were not lysine-lysine cross-links but cross-links between lysine and side chains with alcohols (serine, threonine, tyrosine).

2019-04-01 | PXD010070 | Pride

Examination of matricellular fibrosis and wound healing in a model of pancreatic cancer progression

Project description:Pancreatic ductal adenocarcinoma (PDAC) has the highest amount of stroma when compared to other solid tumors. It is now well known that the stroma plays an important role in supporting pancreatic cancer development and progression and this knowledge has led to the development of potential anti-stromal therapies, some of which have shown synergistic effect in combination with gemcitabine. Despite the acknowledgement of its importance, a granular view of how stromal composition and cross-linking change during the course of PDAC progression remains unfounded. Generally, the fibrosis that occurs in solid tumors appears to be driven primarily by increases in the abundance of fibrillar collagen, whose insolubility is determined by the formation of covalent intermolecular cross-links. Here we have used semi-quantitative proteomics and cross-linked amino acid analysis to characterize the composition and crosslinking status of normal pancreatic and PDAC stroma. In order to mimic the desmoplastic stroma observed in human disease, we utilized the genetically engineered KTC mouse model of PDAC (KrasLSL-G12D/+Tgfbr2flox/+Ptf1a-Cre). We found that highly fibrotic PDACs alter the solubility of their collagen-rich stroma through changes in the abundance of collagen cross-links and supports development of matricellular fibrosis associated with a wound healing response.

| MSV000081553 | MassIVE

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