Single cell analysis of mechanical properties and EMT-related gene expression profiles in cancer fingers

Zou, Heng; Yang, Zihan; Chan, Yuen-San; Yeung, Sung-king Au; Alam, Kowsar; Si, Tongxu; Xu, Tao; Yang, Mengsu

doi:10.1016/j.isci.2022.103917

Cited by 16 publications

(11 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 Notably, the observations that cancer cells with partial or hybrid EMT can move jointly, as well as that leading cells in collective migration undergo EMT, indicated that these EMT and collective migration may be interrelated in cancer metastasis. [14][15][16][17][18] Our study strikingly unraveled the pleiotropic regulatory functions of miR-503 in controlling lung cancer metastasis. Accordingly, miR-503 may represent a promising therapeutic target in lung cancer metastasis to kill two birds with one stone.…”

Section: Discussionmentioning

confidence: 74%

MiR‐503 pleiotropically regulates epithelial‐mesenchymal transition and targets PTK7 to control lung cancer metastasis

et al. 2023

View full text Add to dashboard Cite

Objective In lung cancer patients, most deaths are caused by the distant dissemination of cancer cells. Epithelial–mesenchymal transition (EMT) and collective cell migration are distinct and important mechanisms involved in cancer invasion and metastasis. Additionally, microRNA dysregulation contributes significantly to cancer progression. In this study, we aimed to explore the function of miR‐503 in cancer metastasis. Methods Molecular manipulations (silencing or overexpression) were performed to investigate the biological functions of miR‐503 including migration and invasion. Reorganization of cytoskeleton was assessed using immunofluorescence and the relationship between miR‐503 and downstream protein tyrosine kinase 7 (PTK7) was assessed using quantitative real‐time PCR, immunoblotting, and reporter assays. The tail vein metastatic animal experiments were performed. Results Herein, we demonstrated that the downregulation of miR‐503 confers an invasive phenotype in lung cancer cells and provided in vivo evidence that miR‐503 significantly inhibits metastasis. We found that miR‐503 inversely regulates EMT, identified PTK7 as a novel miR‐503 target, and showed the functional effects of miR‐503 on cell migration and invasion were restored upon reconstitution of PTK7 expression. As PTK7 is a Wnt/planar cell polarity protein crucial for collective cell movement, these results implicated miR‐503 in both EMT and collective migration. However, the expression of PTK7 did not influence EMT induction, suggesting that miR‐503 regulates EMT through mechanisms other than PTK7 inhibition. Furthermore, we discovered that PTK7 mechanistically activates focal adhesion kinase (FAK) and paxillin, thereby controlling the reorganization of the cortical actin cytoskeleton. Conclusion Collectively, miR‐503 is capable of governing EMT and PTK7/FAK signaling independently to control the invasion and dissemination of lung cancer cells, indicating that miR‐503 represents a pleiotropic regulator of cancer metastasis and hence a potential therapeutic target for lung cancer.

show abstract

Section: Discussionmentioning

confidence: 74%

MiR‐503 pleiotropically regulates epithelial‐mesenchymal transition and targets PTK7 to control lung cancer metastasis

et al. 2023

View full text Add to dashboard Cite

show abstract

“…These cells expressed mesenchymal markers (SNAI1, VIM) while still retaining epithelial (CDH1) ones, exhibiting a partial EMT phenotype. 34 Another study using image quantification to track EMT progression revealed a partial EMT phenotype with a unique cytoskeletal signature, consistent with decreased stiffness compared to mesenchymal cells. 35 Tracking the morphological changes upon treatment with EMT-inducing growth factors has helped infer transition rates among different morphological cell states and has been used to develop classifiers to segregate epithelial vs mesenchymal states with 92% accuracy.…”

Section: Molecular and Functional Characterization Of Hybrid E/m Statesmentioning

confidence: 98%

“…For instance, single-cell mechanical investigation and spatial EMT-related gene expression profiling illustrated that leader cells in collective cell migration of A549 lung cancer cells were more elongated and softer (lower Young’s modulus) than the follower ones. These cells expressed mesenchymal markers (SNAI1, VIM) while still retaining epithelial (CDH1) ones, exhibiting a partial EMT phenotype . Another study using image quantification to track EMT progression revealed a partial EMT phenotype with a unique cytoskeletal signature, consistent with decreased stiffness compared to mesenchymal cells .…”

Section: Molecular and Functional Characterization Of Hybrid E/m Statesmentioning

confidence: 99%

Dynamics of Epithelial–Mesenchymal Plasticity: What Have Single-Cell Investigations Elucidated So Far?

et al. 2023

View full text Add to dashboard Cite

Epithelial–mesenchymal plasticity (EMP) is a key driver of cancer metastasis and therapeutic resistance, through which cancer cells can reversibly and dynamically alter their molecular and functional traits along the epithelial–mesenchymal spectrum. While cells in the epithelial phenotype are usually tightly adherent, less metastatic, and drug-sensitive, those in the hybrid epithelial/mesenchymal and/or mesenchymal state are more invasive, migratory, drug-resistant, and immune-evasive. Single-cell studies have emerged as a powerful tool in gaining new insights into the dynamics of EMP across various cancer types. Here, we review many recent studies that employ single-cell analysis techniques to better understand the dynamics of EMP in cancer both in vitro and in vivo. These single-cell studies have underlined the plurality of trajectories cells can traverse during EMP and the consequent heterogeneity of hybrid epithelial/mesenchymal phenotypes seen at both preclinical and clinical levels. They also demonstrate how diverse EMP trajectories may exhibit hysteretic behavior and how the rate of such cell-state transitions depends on the genetic/epigenetic background of recipient cells, as well as the dose and/or duration of EMP-inducing growth factors. Finally, we discuss the relationship between EMP and patient survival across many cancer types. We also present a next set of questions related to EMP that could benefit much from single-cell observations and pave the way to better tackle phenotypic switching and heterogeneity in clinic.

show abstract

“…Lateral confinement can be achieved by narrow channels from 3 to 10 µm wide, [10][11][12] which can mimic single-cell migration. We and others have fabricated vertical confinement devices using a polydimethylsiloxane (PDMS) roof ranging from 3 to 7 µm high, in which cells can migrate collectively and laterally [13,14] and micropost arrays that present vertical post barriers for cells to migrate. [15] The width or the height should be <10 µm to provide actual confinement for single cancer cells.…”

Section: Introductionmentioning

confidence: 99%

High Throughput Confined Migration Microfluidic Device for Drug Screening

Yang

Zhou

et al. 2023

Small

Self Cite

View full text Add to dashboard Cite

Cancer metastasis is the major cause of cancer‐related death. Excessive extracellular matrix deposition and increased stiffness are typical features of solid tumors, creating confined spaces for tumor cell migration and metastasis. Confined migration is involved in all metastasis steps. However, confined and unconfined migration inhibitors are different and drugs available to inhibit confined migration are rare. The main challenges are the modeling of confined migration, the suffering of low throughput, and others. Microfluidic device has the advantage to reduce reagent consumption and enhance throughput. Here, a microfluidic chip that can achieve multi‐function drug screening against the collective migration of cancer cells under confined environment is designed. This device is applied to screen out effective drugs on confined migration among a novel mechanoreceptors compound library (166 compounds) in hepatocellular carcinoma, non‐small lung cancer, breast cancer, and pancreatic ductal adenocarcinoma cells. Three compounds that can significantly inhibit confined migration in pan‐cancer: mitochonic acid 5 (MA‐5), SB‐705498, and diphenyleneiodonium chloride are found. Finally, it is elucidated that these drugs targeted mitochondria, actin polymerization, and cell viability, respectively. In sum, a high‐throughput microfluidic platform for screening drugs targeting confined migration is established and three novel inhibitors of confined migration in multiple cancer types are identified.

show abstract

Single cell analysis of mechanical properties and EMT-related gene expression profiles in cancer fingers

Cited by 16 publications

References 38 publications

MiR‐503 pleiotropically regulates epithelial‐mesenchymal transition and targets PTK7 to control lung cancer metastasis

MiR‐503 pleiotropically regulates epithelial‐mesenchymal transition and targets PTK7 to control lung cancer metastasis

Dynamics of Epithelial–Mesenchymal Plasticity: What Have Single-Cell Investigations Elucidated So Far?

High Throughput Confined Migration Microfluidic Device for Drug Screening

Contact Info

Product

Resources

About