A glitch in the matrix: organ-specific matrisomes in metastatic niches
TL;DR: In this paper, the extracellular matrix (ECM) modifications support metastasis in four frequent metastatic sites (the lung, liver, bone, and brain) and discuss ways in which these modifications are shared between metastatic organs as well as features specific to each location.
About: This article is published in Trends in Cell Biology.The article was published on 2021-08-31. It has received 15 citations till now. The article focuses on the topics: Biology & Extracellular matrix.
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TL;DR: Lavie et al. as discussed by the authors discuss the current understanding of CAF subsets and functions as elucidated by single-cell technologies, their functional plasticity, and their emergent shared and organ-specific features that could potentially be harnessed to design better therapeutic strategies for cancer.
Abstract: Cancer-associated fibroblasts (CAFs) are central players in the microenvironment of solid tumors, affecting cancer progression and metastasis. CAFs have diverse phenotypes, origins and functions and consist of distinct subpopulations. Recent progress in single-cell RNA-sequencing technologies has enabled detailed characterization of the complexity and heterogeneity of CAF subpopulations in multiple tumor types. In this Review, we discuss the current understanding of CAF subsets and functions as elucidated by single-cell technologies, their functional plasticity, and their emergent shared and organ-specific features that could potentially be harnessed to design better therapeutic strategies for cancer. Lavie et al. review the recent advances in the field of cancer-associated fibroblasts, including their tissue-specific complexity and overall plasticity, as revealed by single-cell technologies.
53 citations
TL;DR: The tumor microenvironment (TME) includes diverse immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various additional tissue-resident cell types as discussed by the authors .
21 citations
TL;DR: In this paper , the authors show that systemic treatment with doxorubicin, but not cisplatin, following resection of a triple-negative breast tumor induces the expression of complement factors in lung fibroblasts and modulates an immunosuppressive metastatic niche that supports lung metastasis.
Abstract: Abstract Mortality from breast cancer is almost exclusively a result of tumor metastasis and resistance to therapy and therefore understanding the underlying mechanisms is an urgent challenge. Chemotherapy, routinely used to treat breast cancer, induces extensive tissue damage, eliciting an inflammatory response that may hinder efficacy and promote metastatic relapse. Here we show that systemic treatment with doxorubicin, but not cisplatin, following resection of a triple-negative breast tumor induces the expression of complement factors in lung fibroblasts and modulates an immunosuppressive metastatic niche that supports lung metastasis. Complement signaling derived from cancer-associated fibroblasts (CAFs) mediates the recruitment of myeloid-derived suppressor cells (MDSCs) to the metastatic niche, thus promoting T cell dysfunction. Pharmacological targeting of complement signaling in combination with chemotherapy alleviates immune dysregulation and attenuates lung metastasis. Our findings suggest that combining cytotoxic treatment with blockade of complement signaling in triple-negative breast cancer patients may attenuate the adverse effects of chemotherapy, thus offering a promising approach for clinical use.
17 citations
TL;DR: A variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform are used, to propose a list of promising novel aging-associated targets that may be used for drug discovery and reveal both high confidence and novel targets associated with multiple hallmarks of aging.
Abstract: Aging biology is a promising and burgeoning research area that can yield dual-purpose pathways and protein targets that may impact multiple diseases, while retarding or possibly even reversing age-associated processes. One widely used approach to classify a multiplicity of mechanisms driving the aging process is the hallmarks of aging. In addition to the classic nine hallmarks of aging, processes such as extracellular matrix stiffness, chronic inflammation and activation of retrotransposons are also often considered, given their strong association with aging. In this study, we used a variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform, to propose a list of promising novel aging-associated targets that may be used for drug discovery. We also propose a list of more classical targets that may be used for drug repurposing within each hallmark of aging. Most of the top targets generated by this comprehensive analysis play a role in inflammation and extracellular matrix stiffness, highlighting the relevance of these processes as therapeutic targets in aging and age-related diseases. Overall, our study reveals both high confidence and novel targets associated with multiple hallmarks of aging and demonstrates application of the PandaOmics platform to target discovery across multiple disease areas.
17 citations
TL;DR: In this article , a lung cancer spheroid model with high specificity was used to accurately investigate the cause, metastasis, and treatment strategies for lung cancer in a co-clinical trial with 85% accuracy, 86.7% sensitivity and 80% specificity.
Abstract: Lung cancer remains a major health problem despite the considerable research into prevention and treatment methods. Through a deeper understanding of tumors, patient‐specific ex vivo spheroid models with high specificity can be used to accurately investigate the cause, metastasis, and treatment strategies for lung cancer. Biofabricate lung tumors are presented, consisting of patient‐derived tumor spheroids, endothelial cells, and lung decellularized extracellular matrix, which maintain a radial oxygen gradient, as well as biophysicochemical behaviors of the native tumors for precision medicine. It is also demonstrated that the developed lung‐cancer spheroid model reproduces patient responses to chemotherapeutics and targeted therapy in a co‐clinical trial, with 85% accuracy, 86.7% sensitivity, and 80% specificity. RNA sequencing analysis validates that the gene expression in the spheroids replicates that in the patient's primary tumor. This model can be used as an ex vivo predictive model for personalized cancer therapy and to improve the quality of clinical care.
2 citations
References
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National Taiwan University1, University of Porto2, University of Tokyo3, Rockefeller University4, Memorial Sloan Kettering Cancer Center5, Karolinska Institutet6, Linköping University7, Lawrence Berkeley National Laboratory8, Cornell University9, Alberta Children's Hospital10, Columbia University11, University of Oslo12, University of Nebraska Medical Center13, University of Hamburg14, University of Pennsylvania15, Princeton University16, Rutgers University17, Fred Hutchinson Cancer Research Center18, Carlos III Health Institute19
TL;DR: It is demonstrated that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells.
Abstract: Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
3,399 citations
3,105 citations
TL;DR: A requirement for VEGFR1+ haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells is demonstrated.
Abstract: The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.
2,923 citations
Cornell University1, University of Pennsylvania2, NewYork–Presbyterian Hospital3, Hannover Medical School4, Rockefeller University5, National Taiwan University6, Oslo University Hospital7, University of Oslo8, Memorial Sloan Kettering Cancer Center9, Eppley Institute for Research in Cancer and Allied Diseases10, University of Nebraska Medical Center11
TL;DR: It is shown that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden and suggests that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.
Abstract: Lyden and colleagues report that pancreatic cancer-derived exosomes induce a pre-metastatic niche in the liver by promoting TGFβ secretion from Kupffer cells, leading to fibronectin production in hepatic stellate cells and macrophage recruitment.
1,973 citations
TL;DR: Using scRNA-seq analysis, Bhattacharya and colleagues identify a subset of profibrotic lung macrophages that have a gene expression signature intermediate between those of monocytes and alveolar macrophage.
Abstract: Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in supporting fibrogenesis has not been investigated in vivo. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1+SiglecF+ transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologs of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury.
1,790 citations