A core matrisome gene signature predicts cancer outcome

Yuzhalin, Arseniy E.; Urbonas, Tomas; Silva, Michael A.; Muschel, Ruth J.; Gordon-Weeks, Alex

doi:10.1038/bjc.2017.458

Cited by 92 publications

(89 citation statements)

References 43 publications

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“…b ). This is in accordance with recent findings demonstrating that a large number of matrisome genes are expressed at significantly higher levels in CRC tissues compared to their normal counterparts …”

Section: Resultssupporting

confidence: 93%

“…This is in accordance with recent findings demonstrating that a large number of matrisome genes are expressed at significantly higher levels in CRC tissues compared to their normal counterparts. 14 To investigate whether CRC-HILEC-dependent modulation of the matrisome may affect tumor growth, we took advantage of a 3D in vitro model. For this scope, a microfluidic platform was designed with two parallel adjacent compartments containing cellladen 3D fibrin matrices.…”

Section: Resultsmentioning

confidence: 99%

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Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF11

Ungaro

Colombo

Massimino

et al. 2019

Intl Journal of Cancer

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Colorectal cancer (CRC) is one of the most malignant tumors worldwide. Stromal cells residing in the tumor microenvironment strongly contribute to cancer progression through their crosstalk with cancer cells and extracellular matrix. Here we provide the first evidence that CRC‐associated lymphatic endothelium displays a distinct matrisome‐associated transcriptomic signature, which distinguishes them from healthy intestinal lymphatics. We also demonstrate that CRC‐associated human intestinal lymphatic endothelial cells regulate tumor cell growth via growth differentiation factor 11, a soluble matrisome component which in CRC patients was found to be associated with tumor progression. Our data provide new insights into lymphatic contribution to CRC growth, aside from their conventional role as conduits of metastasis.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF11

Ungaro

Colombo

Massimino

et al. 2019

Intl Journal of Cancer

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“…Two matrisome-gene-based classifiers and their relevance in clinical outcomes have recently been reported [33, 34]. However, technical feasibility and clinical applicability of these gene panels have not been clearly demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Cross-platform meta-analysis reveals common matrisome variation associated with tumor genotypes and immunophenotypes in human cancers

Bin

Jin

Lim

et al. 2018

Preprint

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23Background: Recent sequencing efforts unveil genomic landscapes of the tumor 24 microenvironment. Yet, little is known about the extent to which matrisome pattern is 25 conserved in progressive tumors across diverse cancer types, and thus its clinical impact 26 remains largely unexplored. 27Findings: Using a newly generated, unified data resource, we conducted cross-platform 28 assessment of a measure of altered extra-cellular matrix (ECM) composition and remodeling 29 associated with tumor progression, termed as the matrisome index (TMI). Parallel analyses 30 with TCGA in over 30,000 patient-derived biopsies revealed that TMI is closely associated 31 with mutational load, tumor histopathology, and predictive of patient outcomes. We found an 32 enrichment of specific tumor-infiltrating immune cell populations, signatures predictive of 33 immunotherapy resistance, and several immune checkpoints in tumors with high TMI, 34suggesting potential role of ECM interaction with immunophenotyes and tumor immune 35 escape mechanisms. Both epithelial cancer cells and carcinoma-associated fibroblasts are 36 potential cellular contributors of such deregulated matrisome. 37Conclusions: Despite wide spectrum of genetic heterogeneity and dynamic nature, 38 matrisome abnormalities are integral to disease progression. Our resource of a curated 39 compendium of 8,386 genome-wide profiles, molecular and clinical associations, and 40 matrisome-tumor genotype-immunophenotype relationships identify potentially actionable 41 immune targets that may guide personalized immunotherapy. 42 43We further define the pan-cancer matrisome landscape by exploring previously unknown 69 features of matrix remodeling and their impact on tumor genotypes and immunophenotypes. 70Using this newly curated MMD together with 12 TCGA cohorts, we found robust 71 associations of tumor-promoting matrix composition with genomic instability, molecular and 72 clinical features, and immune infiltrate composition. At the center of our results is the 73 promising clinical applicability of TMI to predict immunotherapeutic responsiveness and the 74 identification of specific immune targets that may be selectively efficacious in subset of 75 matrisome-deregulated carcinomas. 76Results 77 Patterns of deregulated matrisome genes are conserved in various malignancies 78Given that the initial TMI was derived from lung cancer, we first questioned the extent to 79 which genome-wide DE patterns of lung cancer would be shared across various carcinomas. 80Conducting cross-platform analysis with TCGA, we found that DE patterns of lung cancers 81 were comparable to that of breast, ovarian, bladder, colorectal, and prostate cancers, 82 regardless of assayed platforms (Tables S3 and S4). Recent pan-cancer studies have revealed 83 some cancers of these tumor types were classified into common molecular subtypes [8, 9]. 84Assessing the initial 29-matrisome-gene signature at the individual gene level, we found that 85 many genes were consistently positioned in the top of the ranked DE g...

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“…As a cost of degradation, [A] and [I] are reduced at maximum 1.5 unit/MCS in pixels belonging to the ‘lysed’ cell-types. Matrix regeneration is incorporated into the model by conversion of C_Lysed and L_Lysed into C1 (given that cancer cells secrete predominantly fibrillar collagen-rich matrices) after 20 MCS from the degradation event associated with that ‘lysed’ pixel (Socovich and Naba, 2018; Yuzhalin et al, 2018). The regeneration of matrix is essential to eliminate unnecessary free spaces formed as an artefact of matrix degradation which takes the computational model closer to its experimental counterpart.…”

Section: Methodsmentioning

confidence: 99%

An interplay between reaction-diffusion and cell-matrix adhesion regulates multiscale invasion in early breast carcinomatosis

Pally

Pramanik

Bhat

2019

Preprint

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Equal contribution.The progression of cancer in the breast involves multiple reciprocal interactions between malignantly transformed epithelia, surrounding untransformed but affected stromal cells, and the extracellular matrix (ECM) that is remodelled during the process. A quantitative understanding of the relative contribution of such interactions to phenotypes associated with cancer cells can be arrived at through the construction of increasingly complex experimental and computational models. Herein, we introduce a multiscale 3D organo-and patho-typic model that approximates, to an unprecedented extent, the histopathological complexity of a tumor disseminating into its surrounding stromal milieu via both bulk and solitary motility dynamics. End-point and time-lapse microscopic observations of this model allow us to study the earliest steps of cancer invasion as well as the dynamical interactions between the epithelial and stromal compartments. We then construct an agent-based Cellular Potts model that incorporates constituents of the experimental model, as well as places them in similar spatial arrangements. The computational model, which comprises adhesion between cancer cells and the matrices, cell proliferation and apoptosis, and matrix remodeling through reaction-diffusion-based morphogen dynamics, is first trained to phenocopy controls run with the experimental model, wherein one or the other matrices have been removed. The trained computational model successfully predicts phenotypes of the experimental counterparts that are subjected to pharmacological treatments (inhibition of N-linked glycosylation and matrix metalloproteinase activity) and scaffold modulation (alteration of collagen density). Our results suggest that specific permissive regimes of cell-cell and cell-matrix adhesions operating in the context of a reaction-diffusionregulated ECM dynamics, promote multiscale invasion of breast cancer cells and determine the extent to which they migrate through their surrounding stroma. Preparation of cancer cell clusters:Normal/cancer cells were trypsinized using 1:5 diluted 0.25% Trypsin & 0.02% EDTA (HiMedia, TCL007). 30,000 cells per 200 μ L of defined medium (Blaschke et al., 1994) supplemented with 4% rBM (Corning, 354230) were cultured on 3% polyHEMA (Sigma, P3932) coated 96 well plate for 48 hours in a 37 o C humidified incubator with 5% carbon dioxide. 3D invasion assay:rBM-coated clusters were collected into 1.5 mL tubes, centrifuged briefly and supernatant is removed. Acid-extracted rat tail collagen (Gibco, A1048301) was neutralized on ice in the presence of 10X DMEM with 0.1N NaOH such that the final concentration of the collagen is 1 mg/mL. Pellet of clusters was resuspended in 50 μ L of neutralized collagen and seeded in 8-well chambered cover glass (Eppendorf 0030742036) and supplemented with defined medium. 3D cultures were grown in a 37 o C humidified incubator with 5% carbon dioxide. Processing of 3D invasive clusters:3D invasion cultures were washed with phosphate buffered saline pH 7...

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A core matrisome gene signature predicts cancer outcome

Abstract: Here we identify a nine-gene ECM signature, which strongly predicts outcome across multiple cancer types and can be used for prognostication after validation in prospective cancer cohorts.

Cited by 92 publications

References 43 publications

Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF11

Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF11

Cross-platform meta-analysis reveals common matrisome variation associated with tumor genotypes and immunophenotypes in human cancers

An interplay between reaction-diffusion and cell-matrix adhesion regulates multiscale invasion in early breast carcinomatosis

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