Analysis of tumor- and stroma-supplied proteolytic networks in different metastatic tumor microenvironments identifies a critical role for cathepsin S in brain metastasis
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PROVIDER: PRJNA208376 | ENA |
REPOSITORIES: ENA
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Project description:Metastasis is a multistage process that requires cancer cells to escape from the primary tumor, survive in the circulation, seed at distant sites and colonize these foreign tissue environments. Each of these processes involves rate-limiting steps that are influenced by stromal cells of the tumor microenvironment. While the tumor microenvironment has emerged as a major regulator of cancer progression in other organ sites, our knowledge of the brain metastatic microenvironment is currently very limited. Thus, we aim to dissect signatures of tumor-stroma interactions in brain metastasis in order to identify factors that regulate the homing, seeding and outgrowth of cancer cells in this highly specialized microenvironment. We took advantage of an experimental metastasis model in which variants of the human breast cancer line MDA-MB-231 home to the brain in xenografted animals. To simultaneously capture gene expression changes in the tumor and stromal compartment, we used a dual species-specific microarray platform, the HuMuProtIn array, to discriminate between differentially expressed protease or protease inhibitor genes of human (tumor) or murine (stromal) origin. RNA was isolated from early and late brain, bone and lung metastases from xenograft models of breast metastasis. RNA was also isolated from non-tumor-burdened mouse brain, bone and lung as normal tissue controls. RNA from tissue homing cell lines was isolated in vitro to serve as a control for the human-derived RNA. Samples were collected from 24 total tumor-burdened mice, with 3 replicates for each condition and control. A total of 36 samples are included here.
2014-07-04 | E-GEOD-47930 | biostudies-arrayexpress
Project description:Metastasis is a multistage process that requires cancer cells to escape from the primary tumor, survive in the circulation, seed at distant sites and colonize these foreign tissue environments. Each of these processes involves rate-limiting steps that are influenced by stromal cells of the tumor microenvironment. While the tumor microenvironment has emerged as a major regulator of cancer progression in other organ sites, our knowledge of the brain metastatic microenvironment is currently very limited. Thus, we aim to dissect signatures of tumor-stroma interactions in brain metastasis in order to identify factors that regulate the homing, seeding and outgrowth of cancer cells in this highly specialized microenvironment. We took advantage of an experimental metastasis model in which variants of the human breast cancer line MDA-MB-231 home to the brain in xenografted animals. To simultaneously capture gene expression changes in the tumor and stromal compartment, we used a dual species-specific microarray platform, the HuMuProtIn array, to discriminate between differentially expressed protease or protease inhibitor genes of human (tumor) or murine (stromal) origin.
2014-07-04 | GSE47930 | GEO
Project description:Cathepsin L is a lysosomal protease that is secreted by several cancer cells. Cathepsin L upregulation has been widely associated with poor clinical outcome and increased metastatic incidence. However, whether Cathepsin L participates in tumor angiogenesis remains less studied. Our study showed a significant activation of angiogenic capacity of endothelial cells in presence of purified or tumor derived Cathepsin L. In addition, Cathepsin L exposure led to a significant increase in the proliferative capacity of endothelial cells. While the ability of Cathepsin L to promote endothelial cell sprouting, migration, invasion and tube formation can be attributed to its proteolytic effects on extracellular matrix, how it promotes endothelial cell proliferation remains obscure. The objective of this study was to test if Cathepsin L exposure can activate signaling cascades and gene expression leading to proliferation of endothelial cells.
2016-06-20 | GSE75744 | GEO
Project description:Metastasis is a multistage process that requires cancer cells to escape from the primary tumor, survive in the circulation, seed at distant sites and colonize these foreign tissue environments. Each of these processes involves rate-limiting steps that are influenced by stromal cells of the tumor microenvironment. While the tumor microenvironment has emerged as a major regulator of cancer progression in other organ sites, our knowledge of the brain metastatic microenvironment is currently very limited. Thus, we aim to dissect signatures of tumor-stroma interactions in brain metastasis in order to identify factors that regulate the homing, seeding and outgrowth of cancer cells in this highly specialized microenvironment. We took advantage of an experimental metastasis model in which variants of the human breast cancer line MDA-MB-231 home to the brain in xenografted animals. To simultaneously capture gene expression changes in the tumor and stromal compartment, we used a dual species-specific microarray platform, the HuMuProtIn array, to discriminate between differentially expressed protease or protease inhibitor genes of human (tumor) or murine (stromal) origin. RNA was isolated from early and late brain, bone and lung metastases from xenograft models of breast metastasis. RNA was also isolated from non-tumor-burdened mouse brain, bone and lung as normal tissue controls. RNA from tissue homing cell lines was isolated in vitro to serve as a control for the human-derived RNA. Samples were collected from 24 total tumor-burdened mice, with 3 replicates for each condition and control. A total of 36 samples are included here.
| S-ECPF-GEOD-47930 | biostudies-other
Project description:Tumor-associated macrophages (TAMs) have emerged as prominent cells within the tumor microenvironment playing critical roles in extracellular matrix remodeling, tumor cell proliferation and invasion, angiogenesis, and metastasis. Cathepsin proteases, produced by tumor cells and TAMs, have been demonstrated to mediate these processes, but it still remains unclear how these typically lysosomal enzymes are capable of executing their functions in the extracellular space. Here we identify a novel interaction between STAT6 and STAT3 that potently upregulates cathepsin secretion in macrophages in response to TH2 cytokine stimulation. Systematic gene expression analyses reveal that the TH2 cytokine IL-4 synergizes with IL-6 or IL-10 to activate the IRE1α/ XBP1 axis of the unfolded protein response. Pharmacological inhibition of the IRE1α axis blunts cathepsin secretion in macrophages and blocks macrophage-mediated tumor cell invasion. Finally, we show that genetic ablation of either STAT6 or STAT3 signaling impairs tumor development and invasion. Thus, these findings demonstrate that TH2 cytokine-mediated STAT6 and STAT3 activation in macrophages promotes a professional secretory phenotype capable of enhancing tumor cell invasion in a cathepsin-dependent manner.
2016-08-17 | GSE70626 | GEO
Project description:MS-based proteomics study of the cancer secretome and tumor interstitial fluid of tumor cell/macrophage co-cultures and breast tumors in cells and mice lacking both cathepsin B and cathepsin Z
2021-09-08 | PXD015209 | Pride
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Project description:Metastasis remains the most common cause of death in most cancers, with limited therapies for combating disseminated disease. While the primary tumour microenvironment is an important regulator of cancer progression, it is less well understood how different tissue environments influence metastasis. We analysed tumour-stroma interactions that modulate organ tropism of brain, bone and lung metastasis in xenograft models. We identified a number of potential modulators of site-specific metastasis, including cathepsin S as a regulator of breast-to-brain metastasis. High cathepsin S expression at the primary site correlated with decreased brain metastasis-free survival in breast cancer patients. Both macrophages and tumour cells produce cathepsin S, and only the combined depletion significantly reduced brain metastasis in vivo. Cathepsin S specifically mediates blood-brain barrier transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B. Pharmacological inhibition of cathepsin S significantly reduced experimental brain metastasis, supporting its consideration as a therapeutic target for this disease.
| S-EPMC4249762 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) remains resistant to most treatments and demonstrates a complex pathobiology. Here, we deconvolute regional heterogeneity in the human PDAC tumor microenvironment (TME), a long-standing obstacle, to define precise stromal contributions to PDAC progression. Large scale integration of histology-guided multiOMICs profiling with clinical data sets and functional in vitro models uncovered two microenvironmental programs in PDAC that were anchored in fibroblast differentiation states. These sub-tumor microenvironments (subTMEs) co-occurred intratumorally and were spatially confined, producing patient-specific cellular and molecular heterogeneity associated with shortened patient survival. Each subTME was uniquely structured to support discrete aspects of tumor biology: reactive regions rich in activated fibroblast communities were immune-hot and promoted aggressive tumor progression while deserted regions enriched in extracellular matrix supported tumor differentiation yet were markedly chemoprotective. In conclusion, PDAC regional heterogeneity derives from biologically distinct reactive and protective TME elements with a defined, active role in PDAC progression.
2021-08-23 | GSE166571 | GEO