Contractility, focal adhesion orientation, and stress fiber orientation drive cancer cell polarity and migration along wavy ECM substrates

Fischer, R.; Sun, Xiaoyu; Baird, Michelle A.; Hourwitz, Matt; Seo, Bo Ri; Pasapera, Ana M.; Mehta, Shalin B.; Losert, Wolfgang; Fischbach, Claudia; Fourkas, John T.; Waterman, Clare M.

doi:10.1073/pnas.2021135118

Cited by 55 publications

(32 citation statements)

References 77 publications

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“…We determined that BSS treatment reduced VEGF-induced HUVECs migration ( Figures 3B,C ) . Since stress fibers provide the mechanical basis for cell migration ( Fischer et al, 2021 ), we evaluated the effect of BSS on intensity of F-actin stress fibers. As shown in Figures 3D,E , BSS reduced the TNF-α-induced formation of stress fibers, further confirming the role of BSS in regulating EC migration.…”

Section: Resultsmentioning

confidence: 99%

β-Sitosterol Inhibits Rheumatoid Synovial Angiogenesis Through Suppressing VEGF Signaling Pathway

et al. 2022

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Background: Rheumatoid arthritis (RA) is a chronic disabling inflammatory disease that causes synovial angiogenesis in an invasive manner and leads to joint destruction. Currently available pharmacotherapy for RA has unwanted side effects and limitations. Although anti-angiogenic therapy is regarded as a new potential treatment for RA, only a few anti-angiogenic drugs are available. An increasing number of studies have shown that β-sitosterol (BSS) may exert inhibitory effects against angiogenesis. However, the mechanisms involved are still unclear.Methods: Based on the results of the gene set enrichment analysis (GSEA) of the transcriptome data of endothelial cells from RA patients, we evaluated the pharmacological effects of BSS on the tube formation, cell proliferation, and migration of human umbilical vein endothelial cells (HUVECs). Furthermore, the effects of BSS treatment on vascular endothelial growth factor receptor 2 (VEGFR2) were determined using molecular docking and Western blotting. Additionally, in the presence or absence of BSS, synovial angiogenesis and joint destruction of the ankle were investigated in collagen-induced arthritis (CIA) mice. The effect of BSS treatment on VEGFR2/p-VEGFR2 expression was verified through immunohistochemical staining.Results: The immunohistochemistry results revealed that BSS treatment inhibited angiogenesis both in vitro and in vivo. In addition, the results of 5-ethynyl-2′-deoxyuridine and cell cycle analysis showed that BSS treatment suppressed the proliferation of HUVECs, while the Transwell migration and stress fiber assays demonstrated that BSS treatment inhibited the migration of HUVECs. Notably, the inhibitory effect of BSS treatment on VEGFR2/p-VEGFR2 was similar to that of axitinib. In CIA mice, BSS also exerted therapeutic effects on the ankles by reducing the degree of swelling, ameliorating bone and cartilage damage, preventing synovial angiogenesis, and inhibiting VEGFR2 and p-VEGFR2 expression.Conclusion: Therefore, our findings demonstrate that BSS exerts an inhibitory effect on synovial angiogenesis by suppressing the proliferation and migration of endothelial cells, thereby alleviating joint swelling and bone destruction in CIA mice. Furthermore, the underlying therapeutic mechanisms may involve the inhibition of VEGF signaling pathway activation.

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Section: Resultsmentioning

confidence: 99%

β-Sitosterol Inhibits Rheumatoid Synovial Angiogenesis Through Suppressing VEGF Signaling Pathway

et al. 2022

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“…The specific structure of the ECM regulates tumor cells motilities through driving the dynamic re‐organization of cytoskeleton and focal adhesion. [ 37 ] Micromotion indexes measured in more complex gels that better mimic the native ECM of specific tissues is therefore anticipated to be of higher physiological relevance and consequently could yield better biological insight. Further assessment of the correlation between single‐cell migration and MI in presence of chemotractant gradients would also generate interesting insights.…”

Section: Discussionmentioning

confidence: 99%

Optical Cellular Micromotion: A New Paradigm to Measure Tumor Cells Invasion within Gels Mimicking the 3D Tumor Environments

et al. 2022

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Measuring tumor cell invasiveness through 3D tissues, particularly at the single‐cell level, can provide important mechanistic understanding and assist in identifying therapeutic targets of tumor invasion. However, current experimental approaches, including standard in vitro invasion assays, have limited physiological relevance and offer insufficient insight into the vast heterogeneity in tumor cell migration through tissues. To address these issues, here the concept of optical cellular micromotion is reported on, where digital holographic microscopy is used to map the optical nano‐ to submicrometer thickness fluctuations within single‐cells. These fluctuations are driven by the dynamic movement of subcellular structures including the cytoskeleton and inherently associated with the biological processes involved in cell invasion within tissues. It is experimentally demonstrated that the optical cellular micromotion correlates with tumor cells motility and invasiveness both at the population and single‐cell levels. In addition, the optical cellular micromotion significantly reduced upon treatment with migrastatic drugs that inhibit tumor cell invasion. These results demonstrate that micromotion measurements can rapidly and non‐invasively determine the invasive behavior of single tumor cells within tissues, yielding a new and powerful tool to assess the efficacy of approaches targeting tumor cell invasiveness.

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“…5B,ii-v) 103 . Further, Keely and coworkers observed that these fibers exhibited a wavy ("crimped") conformation 104 , which has recently been reported to impede cell polarization 105 and enhance dormancy 106 . The interstitial matrix is occupied by stromal cells (e.g.…”

Section: The Extracellular Matrix and Engineered Biomaterialsmentioning

confidence: 98%

Mechanobiology of Collective Cell Migration in 3D Microenvironments

Hruska¹,

Yang²,

Leggett³

et al. 2022

Preprint

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Tumor cells invade individually or in groups, mediated by mechanical interactions between cells and their surrounding matrix. These multicellular dynamics are reminiscent of leader-follower coordination and epithelial-mesenchymal transitions (EMT) in tissue development, which may occur via dysregulation of associated molecular or physical mechanisms. However, it remains challenging to elucidate such phenotypic heterogeneity and plasticity without precision measurements of single cell behavior. The convergence of technological developments in live cell imaging, biophysical measurements, and 3D biomaterials are highly promising to reveal how tumor cells cooperate in aberrant microenvironments. Here, we highlight new results in collective migration from the perspective of cancer biology and bioengineering. First, we review the biology of collective cell migration. Next, we consider physics-inspired analyses based on order parameters and phase transitions. Further, we examine the interplay of metabolism and heterogeneity in collective migration. We then review the extracellular matrix, and new modalities for mechanical characterization of 3D biomaterials. We also explore epithelial-mesenchymal plasticity and implications for tumor progression. Finally, we speculate on future directions for integrating mechanobiology and cancer cell biology to elucidate collective migration.

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Contractility, focal adhesion orientation, and stress fiber orientation drive cancer cell polarity and migration along wavy ECM substrates

Cited by 55 publications

References 77 publications

β-Sitosterol Inhibits Rheumatoid Synovial Angiogenesis Through Suppressing VEGF Signaling Pathway

β-Sitosterol Inhibits Rheumatoid Synovial Angiogenesis Through Suppressing VEGF Signaling Pathway

Optical Cellular Micromotion: A New Paradigm to Measure Tumor Cells Invasion within Gels Mimicking the 3D Tumor Environments

Mechanobiology of Collective Cell Migration in 3D Microenvironments

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