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1.
Cell ; 176(4): 757-774.e23, 2019 02 07.
Article in English | MEDLINE | ID: mdl-30712866

ABSTRACT

ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206+CD163+ tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages. Both amoeboid cancer cells and their associated macrophages support an abnormal vasculature, which ultimately facilitates tumor progression. Mechanistically, amoeboid cancer cells perpetuate their behavior via ROCK-Myosin II-driven IL-1α secretion and NF-κB activation. Using an array of tumor models, we show that high Myosin II activity in tumor cells reprograms the innate immune microenvironment to support tumor growth. We describe an unexpected role for Myosin II dynamics in cancer cells controlling myeloid function via secreted factors.


Subject(s)
Cell Movement/physiology , Myosin Type II/metabolism , Adult , Aged , Aged, 80 and over , Animals , Cell Adhesion , Cell Line, Tumor , Cell Movement/immunology , Cytoskeletal Proteins , Female , Humans , Interleukin-1alpha/metabolism , Male , Melanoma/pathology , Mice , Mice, Inbred C57BL , Mice, SCID , Middle Aged , NF-kappa B/metabolism , Neoplasms/immunology , Neoplasms/metabolism , Phosphorylation , Proteomics , Receptor Cross-Talk/physiology , Signal Transduction , Tumor Microenvironment/immunology
2.
Environ Sci Technol ; 58(17): 7256-7269, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38641325

ABSTRACT

Through investigating the combined impact of the environmental exposures experienced by an individual throughout their lifetime, exposome research provides opportunities to understand and mitigate negative health outcomes. While current exposome research is driven by epidemiological studies that identify associations between exposures and effects, new frameworks integrating more substantial population-level metadata, including electronic health and administrative records, will shed further light on characterizing environmental exposure risks. Molecular biology offers methods and concepts to study the biological and health impacts of exposomes in experimental and computational systems. Of particular importance is the growing use of omics readouts in epidemiological and clinical studies. This paper calls for the adoption of mechanistic molecular biology approaches in exposome research as an essential step in understanding the genotype and exposure interactions underlying human phenotypes. A series of recommendations are presented to make the necessary and appropriate steps to move from exposure association to causation, with a huge potential to inform precision medicine and population health. This includes establishing hypothesis-driven laboratory testing within the exposome field, supported by appropriate methods to read across from model systems research to human.


Subject(s)
Environmental Exposure , Exposome , Humans , Molecular Biology
3.
Nature ; 560(7716): 55-60, 2018 08.
Article in English | MEDLINE | ID: mdl-30022166

ABSTRACT

Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood-brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor α6 integrin is expressed in most cases of ALL. We found that α6 integrin-laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kδ inhibitor, which decreased α6 integrin expression on ALL cells, or specific α6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that α6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.


Subject(s)
Central Nervous System/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Animals , Antibodies, Neutralizing/immunology , Basement Membrane/metabolism , Blood-Brain Barrier/metabolism , Bone Marrow , Cell Movement , Central Nervous System/blood supply , Central Nervous System/metabolism , Cerebrospinal Fluid/metabolism , Cerebrovascular Circulation , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Disease Progression , Female , Heterografts/immunology , Heterografts/pathology , Integrin alpha6/immunology , Integrin alpha6/metabolism , Laminin/metabolism , Male , Mice , Mice, SCID , Neoplasm Transplantation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Receptors, Laminin/antagonists & inhibitors , Receptors, Laminin/immunology , Receptors, Laminin/metabolism , Skull , Subarachnoid Space
4.
Nucleic Acids Res ; 50(D1): D11-D19, 2022 01 07.
Article in English | MEDLINE | ID: mdl-34850134

ABSTRACT

The European Bioinformatics Institute (EMBL-EBI) maintains a comprehensive range of freely available and up-to-date molecular data resources, which includes over 40 resources covering every major data type in the life sciences. This year's service update for EMBL-EBI includes new resources, PGS Catalog and AlphaFold DB, and updates on existing resources, including the COVID-19 Data Platform, trRosetta and RoseTTAfold models introduced in Pfam and InterPro, and the launch of Genome Integrations with Function and Sequence by UniProt and Ensembl. Furthermore, we highlight projects through which EMBL-EBI has contributed to the development of community-driven data standards and guidelines, including the Recommended Metadata for Biological Images (REMBI), and the BioModels Reproducibility Scorecard. Training is one of EMBL-EBI's core missions and a key component of the provision of bioinformatics services to users: this year's update includes many of the improvements that have been developed to EMBL-EBI's online training offering.


Subject(s)
Computational Biology/education , Computational Biology/methods , Databases, Factual , Academies and Institutes , Artificial Intelligence , COVID-19 , Databases, Factual/economics , Databases, Factual/statistics & numerical data , Databases, Pharmaceutical , Databases, Protein , Europe , Genome, Human , Humans , Information Storage and Retrieval , RNA, Untranslated/genetics , SARS-CoV-2/genetics
5.
Nucleic Acids Res ; 49(D1): D29-D37, 2021 01 08.
Article in English | MEDLINE | ID: mdl-33245775

ABSTRACT

The European Bioinformatics Institute (EMBL-EBI; https://www.ebi.ac.uk/) provides freely available data and bioinformatics services to the scientific community, alongside its research activity and training provision. The 2020 COVID-19 pandemic has brought to the forefront a need for the scientific community to work even more cooperatively to effectively tackle a global health crisis. EMBL-EBI has been able to build on its position to contribute to the fight against COVID-19 in a number of ways. Firstly, EMBL-EBI has used its infrastructure, expertise and network of international collaborations to help build the European COVID-19 Data Platform (https://www.covid19dataportal.org/), which brings together COVID-19 biomolecular data and connects it to researchers, clinicians and public health professionals. By September 2020, the COVID-19 Data Platform has integrated in excess of 170 000 COVID-19 biomolecular data and literature records, collected through a number of EMBL-EBI resources. Secondly, EMBL-EBI has strived to continue its support of the life science communities through the crisis, with updated Training provision and improved service provision throughout its resources. The COVID-19 pandemic has highlighted the importance of EMBL-EBI's core principles, including international cooperation, resource sharing and central data brokering, and has further empowered scientific cooperation.


Subject(s)
COVID-19/prevention & control , Computational Biology/statistics & numerical data , Databases, Nucleic Acid/statistics & numerical data , Information Storage and Retrieval/methods , SARS-CoV-2/genetics , Viral Proteins/genetics , COVID-19/epidemiology , COVID-19/virology , Computational Biology/methods , Computational Biology/organization & administration , Databases, Nucleic Acid/organization & administration , Global Health , Humans , Information Storage and Retrieval/statistics & numerical data , Internet , Pandemics , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Viral Proteins/metabolism
6.
Br J Cancer ; 125(5): 699-713, 2021 08.
Article in English | MEDLINE | ID: mdl-34172930

ABSTRACT

BACKGROUND: Metastasis is a hallmark of cancer and responsible for most cancer deaths. Migrastatics were defined as drugs interfering with all modes of cancer cell invasion and thus cancers' ability to metastasise. First anti-metastatic treatments have recently been approved. METHODS: We used bioinformatic analyses of publicly available melanoma databases. Experimentally, we performed in vitro target validation (including 2.5D cell morphology analysis and mass spectrometric analysis of RhoA binding partners), developed a new traceable spontaneously metastasising murine melanoma model for in vivo validation, and employed histology (haematoxylin/eosin and phospho-myosin II staining) to confirm drug action in harvested tumour tissues. RESULTS: Unbiased and targeted bioinformatic analyses identified the Rho kinase (ROCK)-myosin II pathway and its various components as potentially relevant targets in melanoma. In vitro validation demonstrated redundancy of several RhoGEFs upstream of RhoA and confirmed ROCK as a druggable target downstream of RhoA. The anti-metastatic effects of two ROCK inhibitors were demonstrated through in vivo melanoma metastasis tracking and inhibitor effects also confirmed ex vivo by digital pathology. CONCLUSIONS: We proposed a migrastatic drug development pipeline. As part of the pipeline, we provide a new traceable spontaneous melanoma metastasis model for in vivo quantification of metastasis and anti-metastatic effects by non-invasive imaging.


Subject(s)
Computational Biology/methods , Melanoma/drug therapy , Myosin Type II/metabolism , Protein Kinase Inhibitors/administration & dosage , rho-Associated Kinases/metabolism , rhoA GTP-Binding Protein/metabolism , Animals , Cell Line, Tumor , Cell Movement/drug effects , Humans , Male , Mass Spectrometry , Melanoma/metabolism , Mice , Neoplasm Metastasis , Protein Interaction Maps , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
7.
Semin Cancer Biol ; 42: 60-69, 2017 02.
Article in English | MEDLINE | ID: mdl-27586372

ABSTRACT

The Transforming Growth Factor-beta (TGFß) pathway mediates a broad spectrum of cellular processes and is involved in several diseases, including cancer. TGFß has a dual role in tumours, acting as a tumour suppressor in the early phase of tumorigenesis and as a tumour promoter in more advanced stages. In this review, we discuss the effects of TGFß-driven transcription on all stages of tumour progression, with special focus on lung cancer. Since some TGFß target genes are specifically involved in promoting metastasis, we speculate that these genes might be good targets to block tumour progression without compromising the tumour suppressor effects of the TGFß pathway.


Subject(s)
Cell Transformation, Neoplastic/genetics , Neoplasms/genetics , Transcription, Genetic , Transforming Growth Factor beta/genetics , Genes, Tumor Suppressor , Humans , Neoplasm Staging , Neoplasms/pathology , Signal Transduction/genetics
8.
J Biol Chem ; 288(44): 32093-105, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-24052262

ABSTRACT

Filamins are actin-binding and cross-linking proteins that organize the actin cytoskeleton and anchor transmembrane proteins to the cytoskeleton and scaffold signaling pathways. During hematopoietic cell differentiation, transient expression of ASB2α, the specificity subunit of an E3-ubiquitin ligase complex, triggers acute proteasomal degradation of filamins. This led to the proposal that ASB2α regulates hematopoietic cell differentiation by modulating cell adhesion, spreading, and actin remodeling through targeted degradation of filamins. Here, we show that the calponin homology domain 1 (CH1), within the filamin A (FLNa) actin-binding domain, is the minimal fragment sufficient for ASB2α-mediated degradation. Combining an in-depth flow cytometry analysis with mutagenesis of lysine residues within CH1, we find that arginine substitution at each of a cluster of three lysines (Lys-42, Lys-43, and Lys-135) renders FLNa resistant to ASB2α-mediated degradation without altering ASB2α binding. These lysines lie within previously predicted actin-binding sites, and the ASB2α-resistant filamin mutant is defective in targeting to F-actin-rich structures in cells. However, by swapping CH1 with that of α-actinin1, which is resistant to ASB2α-mediated degradation, we generated an ASB2α-resistant chimeric FLNa with normal subcellular localization. Notably, this chimera fully rescues the impaired cell spreading induced by ASB2α expression. Our data therefore reveal ubiquitin acceptor sites in FLNa and establish that ASB2α-mediated effects on cell spreading are due to loss of filamins.


Subject(s)
Filamins/metabolism , Hematopoietic Stem Cells/metabolism , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Suppressor of Cytokine Signaling Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Filamins/genetics , Humans , Mutation , Proteasome Endopeptidase Complex/genetics , Protein Binding , Protein Structure, Tertiary , Suppressor of Cytokine Signaling Proteins/genetics , Ubiquitin/genetics , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitination/physiology
9.
Nat Rev Cancer ; 21(7): 461-475, 2021 07.
Article in English | MEDLINE | ID: mdl-33953370

ABSTRACT

In contrast to solid cancers, which often require genetic modifications and complex cellular reprogramming for effective metastatic dissemination, leukaemic cells uniquely possess the innate ability for migration and invasion. Dedifferentiated, malignant leukocytes retain the benign leukocytes' capacity for cell motility and survival in the circulation, while acquiring the potential for rapid and uncontrolled cell division. For these reasons, leukaemias, although not traditionally considered as metastatic diseases, are in fact models of highly efficient metastatic spread. Accordingly, they are often aggressive and challenging diseases to treat. In this Perspective, we discuss the key molecular processes that facilitate metastasis in a variety of leukaemic subtypes, the clinical significance of leukaemic invasion into specific tissues and the current pipeline of treatments targeting leukaemia metastasis.


Subject(s)
Leukemia/pathology , Neoplasm Metastasis , Animals , Cell Movement , Cellular Reprogramming , Humans , Leukemia/drug therapy , Neoplasm Invasiveness
10.
Nat Commun ; 11(1): 5315, 2020 10 20.
Article in English | MEDLINE | ID: mdl-33082334

ABSTRACT

Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.


Subject(s)
Frizzled Receptors/metabolism , Melanoma/metabolism , Microfilament Proteins/metabolism , Wnt Proteins/metabolism , rho GTP-Binding Proteins/metabolism , Animals , Cell Transformation, Neoplastic , Female , Frizzled Receptors/genetics , Humans , Male , Melanoma/genetics , Melanoma/pathology , Mice , Mice, SCID , Microfilament Proteins/genetics , Myosin Type II/genetics , Myosin Type II/metabolism , Neoplasm Invasiveness , Signal Transduction , Wnt Proteins/genetics , rho GTP-Binding Proteins/genetics , rho-Associated Kinases/genetics , rho-Associated Kinases/metabolism
11.
F1000Res ; 52016.
Article in English | MEDLINE | ID: mdl-27158478

ABSTRACT

Metastasis is the spread of cancer cells around the body and the cause of the majority of cancer deaths. Metastasis is a very complex process in which cancer cells need to dramatically modify their cytoskeleton and cope with different environments to successfully colonize a secondary organ. In this review, we discuss recent findings pointing at Rho-ROCK or actomyosin force (or both) as major drivers of many of the steps required for metastatic success. We propose that these are important drug targets that need to be considered in the clinic to palliate metastatic disease.

12.
J Natl Cancer Inst ; 108(1)2016 Jan.
Article in English | MEDLINE | ID: mdl-26464464

ABSTRACT

BACKGROUND: Abnormal cell migration and invasion underlie metastasis, and actomyosin contractility is a key regulator of tumor invasion. The links between cancer migratory behavior and DNA damage are poorly understood. METHODS: Using 3D collagen systems to recapitulate melanoma extracellular matrix, we analyzed the relationship between the actomyosin cytoskeleton of migrating cells and DNA damage. We used multiple melanoma cell lines and microarray analysis to study changes in gene expression and in vivo intravital imaging (n = 7 mice per condition) to understand how DNA damage impacts invasive behavior. We used Protein Tissue Microarrays (n = 164 melanomas) and patient databases (n = 354 melanoma samples) to investigate the associations between markers of DNA damage and actomyosin cytoskeletal features. Data were analyzed with Student's and multiple t tests, Mann-Whitney's test, one-way analysis of variance, and Pearson correlation. All statistical tests were two-sided. RESULTS: Melanoma cells with low levels of Rho-ROCK-driven actomyosin are subjected to oxidative stress-dependent DNA damage and ATM-mediated p53 protein stabilization. This results in a specific transcriptional signature enriched in DNA damage/oxidative stress responsive genes, including Tumor Protein p53 Inducible Protein 3 (TP53I3 or PIG3). PIG3, which functions in DNA damage repair, uses an unexpected catalytic mechanism to suppress Rho-ROCK activity and impair tumor invasion in vivo. This regulation was suppressed by antioxidants. Furthermore, PIG3 levels decreased while ROCK1/2 levels increased in human metastatic melanomas (ROCK1 vs PIG3; r = -0.2261, P < .0001; ROCK2 vs PIG3: r = -0.1381, P = .0093). CONCLUSIONS: The results suggest using Rho-kinase inhibitors to reactivate the p53-PIG3 axis as a novel therapeutic strategy; we suggest that the use of antioxidants in melanoma should be very carefully evaluated.


Subject(s)
Actomyosin , Cytoskeleton/metabolism , DNA Damage , DNA Repair , Intracellular Signaling Peptides and Proteins/genetics , Melanoma/genetics , Proto-Oncogene Proteins/genetics , Reactive Oxygen Species/metabolism , Tumor Suppressor Protein p53/genetics , Animals , Cell Line, Tumor , Cytoskeleton/pathology , DNA Damage/genetics , DNA Repair/genetics , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Melanoma/metabolism , Mice , Microscopy, Confocal , Microscopy, Fluorescence , Oxidative Stress , Protein Array Analysis , Tissue Array Analysis , rho-Associated Kinases/metabolism
13.
Curr Biol ; 25(22): 2899-914, 2015 Nov 16.
Article in English | MEDLINE | ID: mdl-26526369

ABSTRACT

Cell migration underlies metastatic dissemination of cancer cells, and fast "amoeboid" migration in the invasive fronts of tumors is controlled by high levels of actomyosin contractility. How amoeboid migration is regulated by extracellular signals and sustained over time by transcriptional changes is not fully understood. Transforming growth factor ß (TGF-ß) is well known to promote epithelial-to-mesenchymal transition (EMT) and contribute to metastasis, but melanocytes are neural crest derivatives that have undergone EMT during embryonic development. Surprisingly, we find that in melanoma, TGF-ß promotes amoeboid features such as cell rounding, membrane blebbing, high levels of contractility, and increased invasion. Using genome-wide transcriptomics, we find that amoeboid melanoma cells are enriched in a TGF-ß-driven signature. We observe that downstream of TGF-ß, SMAD2 and its adaptor CITED1 control amoeboid behavior by regulating the expression of key genes that activate contractile forces. Moreover, CITED1 is highly upregulated during melanoma progression, and its high expression is associated with poor prognosis. CITED1 is coupled to a contractile-rounded, amoeboid phenotype in a panel of 16 melanoma cell lines, in mouse melanoma xenografts, and in 47 human melanoma patients. Its expression is also enriched in the invasive fronts of lesions. Functionally, we show how the TGF-ß-SMAD2-CITED1 axis promotes different steps associated with progression: melanoma detachment from keratinocytes, 2D and 3D migration, attachment to endothelial cells, and in vivo lung metastatic initial colonization and outgrowth. We propose a novel mechanism by which TGF-ß-induced transcription sustains actomyosin force in melanoma cells and thereby promotes melanoma progression independently of EMT.


Subject(s)
Cell Movement/physiology , Melanoma/genetics , Melanoma/pathology , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Actomyosin/metabolism , Animals , Apoptosis Regulatory Proteins , Cell Line, Tumor , Cell Movement/genetics , Cell Shape/physiology , Epithelial-Mesenchymal Transition , Humans , Keratinocytes/metabolism , Melanocytes/metabolism , Melanocytes/pathology , Melanoma/metabolism , Mice , Mice, Nude , Neoplasm Metastasis , Nuclear Proteins/metabolism , Smad2 Protein/metabolism , Trans-Activators , Transcription Factors/metabolism , Transcriptional Activation , Transforming Growth Factor beta/pharmacology , Up-Regulation
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