Exosomes are small microvesicles secreted from the late endosomal compartment of cells. Although an increasing body of evidence indicates that they play a pivotal role in cell‐to‐cell communication, ...the biological functions of exosomes are far from fully understood. Recent work has revealed detailed proteomic profiles of exosomes from cell lines and body fluids, which may provide clues to understanding their biological significance and general importance in human diseases. Metalloproteinases include the cell surface‐anchored sheddases a disintegrin and metalloproteinases, as well as cell surface‐bound and soluble matrix metalloproteinases and these extracellular proteases have been detected in exosomes by proteomic analyses. Exosomes play a key role in the transfer of proteins to other cells and metalloproteinases may provide a novel platform where ectodomain shedding by these membrane proteases alters the makeup of the recipient cell's surface. This review aims to address some of the facets of exosome biology with particular emphasis on the proteolytic factors and we discuss their potential involvement in human diseases, especially tumor biology.
Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. Here, we deconvolute the human pancreatic TME through ...large-scale integration of histology-guided regional multiOMICs with clinical data and patient-derived preclinical models. We discover “subTMEs,” histologically definable tissue states anchored in fibroblast plasticity, with regional relationships to tumor immunity, subtypes, differentiation, and treatment response. “Reactive” subTMEs rich in complex but functionally coordinated fibroblast communities were immune hot and inhabited by aggressive tumor cell phenotypes. The matrix-rich “deserted” subTMEs harbored fewer activated fibroblasts and tumor-suppressive features yet were markedly chemoprotective and enriched upon chemotherapy. SubTMEs originated in fibroblast differentiation trajectories, and transitory states were notable both in single-cell transcriptomics and in situ. The intratumoral co-occurrence of subTMEs produced patient-specific phenotypic and computationally predictable heterogeneity tightly linked to malignant biology. Therefore, heterogeneity within the plentiful, notorious pancreatic TME is not random but marks fundamental tissue organizational units.
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•PDAC regional heterogeneity stems from sub-tumor microenvironments (subTMEs)•SubTMEs exhibit distinct immune phenotypes and CAF differentiation states•SubTMEs execute distinct tumor-promoting and chemoprotective functions•Intratumoral subTME co-occurrence links stromal heterogeneity to patient outcome
Intratumoral heterogeneity in the human pancreatic tumor microenvironment is not random but originates in well-definable regional tissue states. The underlying sub-tumor microenvironments shape regional epithelial and immune phenotypes and influence key clinical metrics of disease progression.
To determine the impact of basal-like and classical subtypes in advanced pancreatic ductal adenocarcinoma (PDAC) and to explore GATA6 expression as a surrogate biomarker.
Within the COMPASS trial, ...patients proceeding to chemotherapy for advanced PDAC undergo tumor biopsy for RNA-sequencing (RNA-seq). Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of
with the subtypes using gene expression profiling,
hybridization (ISH) was explored.
Between December 2015 and May 2019, 195 patients (95%) had enough tissue for RNA-seq; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% versus 33%, respectively (
= 0.02). In patients with basal-like tumors treated with modified FOLFIRINOX (
= 22), the progression rate was 60% compared with 15% in classical PDAC (
= 0.0002). Median OS in the intention-to-treat population (
= 195) was 9.3 months for classical versus 5.9 months for basal-like PDAC (HR, 0.47; 95% confidence interval, 0.32-0.69;
= 0.0001).
expression by RNA-seq highly correlated with the classifier (
< 0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariate analysis, GATA6 expression was prognostic (
= 0.02). In exploratory analyses, basal-like tumors, could be identified by keratin 5, were more hypoxic and enriched for a T-cell-inflamed gene expression signature.
The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression.
.
The mammary gland experiences substantial remodeling and regeneration during development and reproductive life, facilitated by stem cells and progenitors that act in concert with physiological ...stimuli. While studies have focused on deciphering regenerative cells within the parenchymal epithelium, cell lineages in the stroma that may directly contribute to epithelial biology is unknown. Here we identify, in mouse, the transition of a PDGFRα
mesenchymal cell population into mammary epithelial progenitors. In addition to being adipocyte progenitors, PDGFRα
cells make a de novo contribution to luminal and basal epithelia during mammary morphogenesis. In the adult, this mesenchymal lineage primarily generates luminal progenitors within lobuloalveoli during sex hormone exposure or pregnancy. We identify cell migration as a key molecular event that is activated in mesenchymal progenitors in response to epithelium-derived chemoattractant. These findings demonstrate a stromal reservoir of epithelial progenitors and provide insight into cell origins and plasticity during mammary tissue growth.
Breast cancer is one of the most common cancers in humans and will on average affect up to one in eight women in their lifetime in the United States and Europe. The Women's Health Initiative and the ...Million Women Study have shown that hormone replacement therapy is associated with an increased risk of incident and fatal breast cancer. In particular, synthetic progesterone derivatives (progestins) such as medroxyprogesterone acetate (MPA), used in millions of women for hormone replacement therapy and contraceptives, markedly increase the risk of developing breast cancer. Here we show that the in vivo administration of MPA triggers massive induction of the key osteoclast differentiation factor RANKL (receptor activator of NF- B ligand) in mammary-gland epithelial cells. Genetic inactivation of the RANKL receptor RANK in mammary-gland epithelial cells prevents MPA-induced epithelial proliferation, impairs expansion of the CD49fhi stem-cell-enriched population, and sensitizes these cells to DNA-damage-induced cell death. Deletion of RANK from the mammary epithelium results in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. These data show that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer.
Cancer-associated fibroblasts (CAFs) drive tumour progression, but the emergence of this cell state is poorly understood. A broad spectrum of metalloproteinases, controlled by the Timp gene family, ...influence the tumour microenvironment in human cancers. Here, we generate quadruple TIMP knockout (TIMPless) fibroblasts to unleash metalloproteinase activity within the tumour-stromal compartment and show that complete Timp loss is sufficient for the acquisition of hallmark CAF functions. Exosomes produced by TIMPless fibroblasts induce cancer cell motility and cancer stem cell markers. The proteome of these exosomes is enriched in extracellular matrix proteins and the metalloproteinase ADAM10. Exosomal ADAM10 increases aldehyde dehydrogenase expression in breast cancer cells through Notch receptor activation and enhances motility through the GTPase RhoA. Moreover, ADAM10 knockdown in TIMPless fibroblasts abrogates their CAF function. Importantly, human CAFs secrete ADAM10-rich exosomes that promote cell motility and activate RhoA and Notch signalling in cancer cells. Thus, Timps suppress cancer stroma where activated-fibroblast-secreted exosomes impact tumour progression.
Metalloproteinases in extracellular vesicles Shimoda, Masayuki; Khokha, Rama
Biochimica et biophysica acta. Molecular cell research,
November 2017, 2017-Nov, 2017-11-00, 20171101, Letnik:
1864, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Extracellular vesicles (EVs) have emerged as pivotal mediators of intercellular communications in local and distant microenvironments under patho/physiological conditions. EVs contain bioactive ...materials such as proteins, RNA transcripts, microRNAs and even DNAs, and recent work on their protein profiles has revealed the existence of metalloproteinases including the cell surface-anchored sheddases ADAMs (a disintegrin and metalloproteinases) and soluble ADAMTSs (ADAMs with thrombospondin motifs) as well as cell surface-bound and soluble MMPs (matrix metalloproteinases) from various cell types and body fluids. EV-associated metalloproteinases can alter the make-up of EVs by ectodomain shedding, exert a shedding activity after being taken up by target cells, or directly contribute to degradation of extracellular matrix surrounding cells. In addition, metalloproteinase-loaded EV cargoes sometimes stimulate critical signaling pathways, actively participating in tumor progression. This review focuses on recent findings and knowledge about metalloproteinases in EV biology, and we discuss their potential involvement in human diseases, highlighting the context of tumor cells and their microenvironment. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.
•Metalloproteinases have been identified in extracellular vesicles (EVs).•Metalloproteinases in EVs have been detected in various body fluids.•Several metalloproteinases in EVs hold proteolytic activities and alter EV contents.•Metalloproteinases in EVs affect target cells and contribute to ECM degradation.•Metalloproteinases in EVs actively participate in tumor progression.
The metalloproteinase family includes MMP, ADAM and ADAMTS proteases. Mice deficient in individual or pairs of metalloproteinases have been generated, and a number of these genetic models ...spontaneously develop skeletal abnormalities. Here we review metalloproteinase function in endochondral and intramembranous ossification, as well as in postnatal bone remodeling. We highlight how metalloproteinases enable interactions between distinct bone cell types and how this communication contributes to the skeletal phenotypes observed in knockout mice. In addition to the physiological actions of metalloproteinases in the skeletal system, the experimental manipulation of metalloproteinase-deficient mice has revealed substantial roles for these enzymes in osteoarthritis and rheumatoid arthritis. MMP, ADAM and ADAMTS proteases thus emerge as key players in the development and homeostasis of the skeletal system.
Tissue inhibitors of metalloproteinases (TIMPs) are classically known for regulating members of the metzincin protease family and are well recognized for their inhibitory effects in cancer ...development and progression. Despite their common evolutionary structure, the four TIMP proteins have unique properties and regulation, and produce distinct phenotypes when ablated. A comprehensive assessment of their function during tumorigenesis reveals substantial effects on cell proliferation, apoptosis, angiogenesis, invasion, and metastasis as well as a potential role in genomic instability. The TIMPs universally inhibit angiogenesis, invasion, and metastasis, but their specific effects on cell proliferation and apoptosis are both tissue specific and context dependent. They exert these effects in a metalloproteinase-dependent as well as metalloproteinase-independent manner. Knowledge gained from these biological studies provides a foundation for the full understanding of TIMP function in physiology and various pathologies as well as for the development of the next generation of therapeutic metalloproteinase inhibitors.
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