Biology subjects

Shimshoni, E.

Publications and source records attributed to Shimshoni, E..

4 recordsLinked to original sources

bioRxiv2023

Concerted epithelial and stromal changes during progression of Barrett's Esophagus to invasive adenocarcinoma exposed by multi-scale, multi-omics analysis

Esophageal adenocarcinoma arises from Barretts esophagus, a precancerous metaplastic replacement of squamous by columnar epithelium in response to chronic inflammation. Multi-omics profiling, integrating single-cell transcriptomics, extracellular matrix proteomics, tissue-mechanics and spatial proteomics of 64 samples from 12 patients paths of progression from squamous epithelium through metaplasia, dysplasia to adenocarcinoma, revealed shared and patient-specific progression characteristics. The classic metaplastic replacement of epithelial cells was paralleled by metaplastic changes in stromal cells, ECM and tissue stiffness. Strikingly, this change in tissue state at metaplasia was already accompanied by appearance of fibroblasts with characteristics of carcinoma-associated fibroblasts and of an NK cell-associated immunosuppressive microenvironment. Thus, Barretts esophagus progresses as a coordinated multi-component system, supporting treatment paradigms that go beyond targeting cancerous cells to incorporating stromal reprogramming. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/544265v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@64c375org.highwire.dtl.DTLVardef@15c6ef2org.highwire.dtl.DTLVardef@177dee0org.highwire.dtl.DTLVardef@c945e7_HPS_FORMAT_FIGEXP M_FIG Graphical AbstractTo obtain a comprehensive picture of the coordinated changes in epithelial, stromal and immune compartments during development of Barretts-associated esophageal adenocarcinoma, patient-matched samples corresponding to various phases of disease progression were collected from 12 patients, each of which had at a given time point lesions at multiple stages progression (matched-normal, metaplasia, dysplasia, and carcinoma). Matched "normal" gastric tissues were also collected. These sample were analyzed by single cell RNA-sequencing (scRNAseq) for single-cell resolution transcriptomics and Copy Number Variant (CNV), by proteomics for extracellular matrix (ECM) proteins, by Atomic Force Microscopy (AFM for tissue stiffness and by CODEX spatial proteomics imaging The integrative multi-omics analysis exposed drastic alterations in cell type composition and shifts in cell states in all three compartments. A large subpopulation of fibroblasts absent in the normal esophagus and characteristic of dysplasia and adenocarcinoma sample, that based on markers would indeed be considered cancer associated fibroblasts (CAF), appeared already in the metaplastic phase. This fibroblast subpopulation had transcriptomes virtually indistinguishable with fibroblasts of the cancer free gastric epithelium in these patients C_FIG

cancer biology↗

bioRxiv2022

De-tensioning of collagen fibers optimizes endometrial receptivity and improves the rate of embryo implantation

Successful embryo implantation within the uterine wall requires intricate endometrial remodeling. Impaired endometrial receptivity, a common cause of infertility, often results from ineffective remodeling processes. Here, we demonstrate that a single dose of human collagenase-1 administered into the mouse uterus enhances embryo implantation rates. Mechanistically, collagenase-1 induces remodeling of the endometrial extracellular matrix (ECM), leading to the degradation of collagen fibers and proteoglycans. This process releases matrix-bound bioactive factors, such as VEGF, which facilitates local vascular permeability and angiogenesis. Furthermore, collagenase-1 treatment increases NK cell infiltration and elevates levels of the cytokine LIF, a key factor in embryo implantation. Remarkably, the overall structural integrity of the uterine tissue remains uncompromised, even in the presence of reduced tension in endometrial collagen fibers. To assess pre-clinical potential, in-uteri application of collagenase-1 successfully rescued implantation in mouse models subjected to heat stress and embryo transfer, conditions known for their adverse impact on implantation rates. Importantly, ex-vivo exposure of human uterine tissue to collagenase-1 induced collagen de-tensioning and the release of VEGF, demonstrating similar processes observed in the mouse settings, and the potential relevance of this treatment to human conditions. Our findings underscore the immense clinical potential and feasibility of collagenase treatment to enhance uterine receptivity for embryo implantation, offering a controlled and minimally invasive intervention. This innovative approach not only demonstrates the potential to enhance efficiency in livestock breeding but, more importantly, signifies a substantial promise in supporting medical interventions for human reproduction in clinical settings.

biochemistry↗

bioRxiv2020

Integrated metabolomics and proteomics of symptomatic and early pre-symptomatic states of colitis

Two murine models for colitis were used to study multi-level changes and derive molecular signatures of colitis onset and development. By combining metabolomics data on tissues and fecal extracts with proteomics data on tissues, we provide a comprehensive picture of the metabolic profile of acute and chronic states of the disease, and most importantly, of two early pre-symptomatic states. We show that, increased anaerobic glycolysis, accompanied by altered TCA cycle and oxidative phosphorylation, associates with inflammation-induced hypoxia taking place in colon tissues. We also demonstrate significant changes in the metabolomic profiles of fecal extracts in different colitis states, most likely associated with the dysbiosis characteristic of colitis, as well as the dysregulated tissue metabolism. Most remarkably, strong and distinctive tissue and fecal metabolomic signatures can be detected before onset of symptoms. These results highlight the diagnostic potential of global metabolomics for inflammatory diseases.

biochemistry↗

bioRxiv2019

Multidimensional extracellular-matrix analysis reveals a silent pre-clinical signature in inflammatory disease

Identification of early processes leading to complex tissue pathologies, such as inflammatory bowel diseases, poses a major scientific and clinical challenge that is imperative for improved diagnosis and treatment. Most studies of inflammation onset focus on cellular processes and signaling molecules, while overlooking the environment in which they take place, the continuously remodeled extracellular matrix. In this study, we used colitis models for investigating extracellular-matrix dynamics during disease onset, while treating the matrix as a complete and defined entity. Through the analysis of matrix structure, stiffness and composition, we unexpectedly revealed that even prior to the first clinical symptoms, the colon displays its own unique extracellular-matrix signature and found specific markers of clinical potential, which were also validated in human subjects. We also show that the emergence of this pre-symptomatic matrix is mediated by sub-clinical infiltration of neutrophils and monocytes bearing remodeling enzymes. Remarkably, whether the inflammation is chronic or acute, its matrix signature converges at pre-symptomatic states. We suggest that the existence of a pre-symptomatic extracellular-matrix is general and relevant to a wide range of diseases.

systems biology↗