Soft drug-resistant ovarian cancer cells migrate via two distinct mechanisms utilizing myosin II-based contractility

Kapoor, Aastha; Barai, Amlan; Thakur, Bhushan; Das, Alakesh; Patwardhan, Sejal; Monteiro, Melissa; Gaikwad, Snehal; Mogha, Pankaj; Majumder, Abhijit; De, Abhijit; Ray, Pritha; Sen, Shamik

doi:10.1016/j.bbamcr.2017.11.012

Cited by 22 publications

(17 citation statements)

References 65 publications

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“…In addition, cisplatin-sensitive OCCs (A2780) showed a dose-dependent increase in cell stiffness after cisplatin treatment, while resistant cells (A7890cis) were unaffected. However, one study showed that cisplatin- and paclitaxel-resistant OCCs were softer than drug-sensitive cells ( Kapoor et al, 2018 ). Seo et al (2015) found that there was a bimodal distribution in the histogram of mechanical stiffness.…”

Section: Discussionmentioning

confidence: 99%

Substrate Stiffness Modulates the Growth, Phenotype, and Chemoresistance of Ovarian Cancer Cells

Fan

Sun

et al. 2021

Front. Cell Dev. Biol.

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Mechanical factors in the tumor microenvironment play an important role in response to a variety of cellular activities in cancer cells. Here, we utilized polyacrylamide hydrogels with varying physical parameters simulating tumor and metastatic target tissues to investigate the effect of substrate stiffness on the growth, phenotype, and chemotherapeutic response of ovarian cancer cells (OCCs). We found that increasing the substrate stiffness promoted the proliferation of SKOV-3 cells, an OCC cell line. This proliferation coincided with the nuclear translocation of the oncogene Yes-associated protein. Additionally, we found that substrate softening promoted elements of epithelial-mesenchymal transition (EMT), including mesenchymal cell shape changes, increase in vimentin expression, and decrease in E-cadherin and β-catenin expression. Growing evidence demonstrates that apart from contributing to cancer initiation and progression, EMT can promote chemotherapy resistance in ovarian cancer cells. Furthermore, we evaluated tumor response to standard chemotherapeutic drugs (cisplatin and paclitaxel) and found antiproliferation effects to be directly proportional to the stiffness of the substrate. Nanomechanical studies based on atomic force microscopy (AFM) have revealed that chemosensitivity and chemoresistance are related to cellular mechanical properties. The results of cellular elastic modulus measurements determined by AFM demonstrated that Young’s modulus of SKOV-3 cells grown on soft substrates was less than that of cells grown on stiff substrates. Gene expression analysis of SKOV-3 cells showed that mRNA expression can be greatly affected by substrate stiffness. Finally, immunocytochemistry analyses revealed an increase in multidrug resistance proteins, namely, ATP binding cassette subfamily B member 1 and member 4 (ABCB1 and ABCB4), in the cells grown on the soft gel resulting in resistance to chemotherapeutic drugs. In conclusion, our study may help in identification of effective targets for cancer therapy and improve our understanding of the mechanisms of cancer progression and chemoresistance.

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Section: Discussionmentioning

confidence: 99%

Substrate Stiffness Modulates the Growth, Phenotype, and Chemoresistance of Ovarian Cancer Cells

Fan

Sun

et al. 2021

Front. Cell Dev. Biol.

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“… 13 , 17 There is evidence that cisplatin-resistant ovarian cancer cells are mechanically stiffer than their cisplatin-sensitive counterparts. 13 , 17 , 18 …”

Section: Discussionmentioning

confidence: 99%

Mechanical Alteration Associated With Chemotherapeutic Resistance of Breast Cancer Cells

Park

2018

J Cancer Prev

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BackgroundThe mechanical deformability of cancer cells has attracted particular attention as an emerging biomarker for the prediction of anti-cancer drug sensitivity. Nevertheless, it has not been possible to establish a general rubric for the identification of drug susceptibility in breast cancer cells from a mechanical perspective. In the present study, we investigated the mechanical alteration associated with resistance to adjuvant therapy in breast cancer cells.MethodsWe performed an ‘atomic force microscopy (AFM)-based nanomechanical study’ on ‘drug-sensitive (MCF-7)’ and ‘drug-resistant (MCF-7/ADR)’ breast cancer cells. We also conducted cell viability tests to evaluate the difference in doxorubicin responsiveness between two breast cancer cell lines. We carried out a wound closure experiment to investigate the motility changes associated with chemotherapeutic resistance. To elucidate the changes in molecular alteration that accompany chemotherapeutic resistance, we investigated the expression of vinculin and integrin-linked kinase-1–which are proteins involved in substrate adhesion and the actin cytoskeleton–using Western blotting analysis.ResultsA MTT assay confirmed that the dose-dependent efficacy of doxorubicin was reduced in MCF-7/ADR cells compared to that in MCF-7 cells. The wound assay revealed enhanced two-dimensional motility in the MCF-7/ADR cells. The AFM mechanical assay showed evidence that the drug-resistant breast cancer cells exhibited a significant decrease in mechanical deformability compared to their drug-sensitive counterparts. The mechanical alteration in the MCF-7/ADR cells was accompanied by upregulated vinculin expression.ConclusionsThe obtained results manifestly showed that the altered mechanical signatures–including mechanical deformability and motility–were closely related with drug resistance in the breast cancer cells. We believe that this investigation has improved our understanding of the chemotherapeutic susceptibility of breast cancer cells.

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“…Increased confinement led to an increase of cell migration speed associated to a round morphology (354). Chemo-resistant migrating ovarian cancer cells were more contractile and exhibited a rounder morphology while ROCK2-Myosin II mediated nuclear movement and proteolysis in confined environments (355). Breast cancer cells in wider channels migrated using RAC-driven elongated-mesenchymal movement, but when challenged through narrow micro-channels, they displayed blebs, an amoeboid phenotype and faster migration (356).…”

Section: A2 C) Role Of Rho Gtpases In Confined Migrationmentioning

confidence: 99%

Rho GTPase signaling in cancer progression and dissemination

Crosas‐Molist

Samain

Kohlhammer

et al. 2022

Physiological Reviews

104

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Rho GTPases are a family of small G proteins that regulate a wide array of cellular processes related to their key roles controlling the cytoskeleton. On the other hand, cancer is a multi-step disease caused by the accumulation of genetic mutations and epigenetic alterations, from the initial stages of cancer development when cells in normal tissues undergo transformation, to the acquisition of invasive and metastatic traits, responsible for a large number of cancer related deaths. In this review, we discuss the role of Rho GTPase signalling in cancer in every step of disease progression. Rho GTPases contribute to tumour initiation and progression, by regulating proliferation and apoptosis, but also metabolism, senescence and cell stemness. Rho GTPases play a major role in cell migration, and in the metastatic process. They are also involved in interactions with the tumour microenvironment and regulate inflammation, contributing to cancer progression. After years of intensive research, we highlight the importance of relevant models in the Rho GTPase field, and we reflect on the therapeutic opportunities arising for cancer patients.

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Soft drug-resistant ovarian cancer cells migrate via two distinct mechanisms utilizing myosin II-based contractility

Cited by 22 publications

References 65 publications

Substrate Stiffness Modulates the Growth, Phenotype, and Chemoresistance of Ovarian Cancer Cells

Substrate Stiffness Modulates the Growth, Phenotype, and Chemoresistance of Ovarian Cancer Cells

Mechanical Alteration Associated With Chemotherapeutic Resistance of Breast Cancer Cells

Rho GTPase signaling in cancer progression and dissemination

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