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Single Cell Mechanotype and Associated Molecular Changes in Urothelial Cell Transformation and Progression.

ABSTRACT: Cancer cell mechanotype changes are newly recognized cancer phenotypic events, whereas metastatic cancer cells show decreased cell stiffness and increased deformability relative to normal cells. To further examine how cell mechanotype changes in early stages of cancer transformation and progression, an in vitro multi-step human urothelial cell carcinogenic model was used to measure cellular Young's modulus, deformability, and transit time using single-cell atomic force microscopy, microfluidic-based deformability cytometry, and quantitative deformability cytometry, respectively. Measurable cell mechanotype changes of stiffness, deformability, and cell transit time occur early in the transformation process. As cells progress from normal, to preinvasive, to invasive cells, Young's modulus of stiffness decreases and deformability increases gradually. These changes were confirmed in three-dimensional cultured microtumor masses and urine exfoliated cells directly from patients. Using gene screening and proteomics approaches, we found that the main molecular pathway implicated in cell mechanotype changes appears to be epithelial to mesenchymal transition.

SUBMITTER: Yu W

PROVIDER: S-EPMC7711308 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Single Cell Mechanotype and Associated Molecular Changes in Urothelial Cell Transformation and Progression.

Yu Weibo W Lu Qing-Yi QY Sharma Shivani S Ly Chau C Di Carlo Dino D Rowat Amy C AC LeClaire Michael M Kim Donghyuk D Chow Christine C Gimzewski James K JK Rao Jianyu J

Frontiers in cell and developmental biology 20201119

Cancer cell mechanotype changes are newly recognized cancer phenotypic events, whereas metastatic cancer cells show decreased cell stiffness and increased deformability relative to normal cells. To further examine how cell mechanotype changes in early stages of cancer transformation and progression, an <i>in vitro</i> multi-step human urothelial cell carcinogenic model was used to measure cellular Young's modulus, deformability, and transit time using single-cell atomic force microscopy, microfl ...[more]

PMID: 33330495

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Project description:BackgroundMusculoskeletal tissue degeneration impairs the life quality and motor function of many people, especially seniors and athletes. Tendinopathy is one of the most common diseases associated with musculoskeletal tissue degeneration, representing a major global healthcare burden that affects both athletes and the general population, with the clinical presentation of long-term recurring chronic pain and decreased tolerance to activity. The cellular and molecular mechanisms at the basis of the disease process remain elusive. Here, we use a single-cell and spatial RNA sequencing approach to provide a further understanding of cellular heterogeneity and molecular mechanisms underlying tendinopathy progression.ResultsTo explore the changes in tendon homeostasis during the tendinopathy process, we built a cell atlas of healthy and diseased human tendons using single-cell RNA sequencing of approximately 35,000 cells and explored the variations of cell subtypes' spatial distributions using spatial RNA sequencing. We identified and localized different tenocyte subpopulations in normal and lesioned tendons, found different differentiation trajectories of tendon stem/progenitor cells in normal/diseased tendons, and revealed the spatial location relationship between stromal cells and diseased tenocytes. We deciphered the progression of tendinopathy at a single-cell level, which is characterized by inflammatory infiltration, followed by chondrogenesis and finally endochondral ossification. We found diseased tissue-specific endothelial cell subsets and macrophages as potential therapeutic targets.ConclusionsThis cell atlas provides the molecular foundation for investigating how tendon cell identities, biochemical functions, and interactions contributed to the tendinopathy process. The discoveries revealed the pathogenesis of tendinopathy at single-cell and spatial levels, which is characterized by inflammatory infiltration, followed by chondrogenesis, and finally endochondral ossification. Our results provide new insights into the control of tendinopathy and potential clues to developing novel diagnostic and therapeutic strategies.

Dataset Information

Single Cell Mechanotype and Associated Molecular Changes in Urothelial Cell Transformation and Progression.

Publications

Single Cell Mechanotype and Associated Molecular Changes in Urothelial Cell Transformation and Progression.

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