Targeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthma

Sundaram, Aparna; Chen, Chun; Khalifeh-Soltani, Amin; Atakilit, Amha; Ren, Xin; Qiu, Wenli; Jo, Hyunil; DeGrado, William F.; Huang, Xiaozhu; Sheppard, Dean

doi:10.1172/jci88555

Cited by 24 publications

(25 citation statements)

References 48 publications

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“…To validate the function of EV-derived α5β1 observed ex vivo , we first pre-treated EVs from TRAMP mice with ATN-161, an inhibitory peptide to the α5β1 integrin, before incubating them with PC3 cells and assessing their anchorage-independent growth. The concentration of ATN-161 (100 μg/mL) has been previously validated by another group while studying mouse α5β1 function in vitro (Sundaram et al., 2017). Colonies whose sizes were ≥25 μm were quantified and expressed as a percent of the total number of colonies.…”

Section: Resultsmentioning

confidence: 99%

Tumor-Derived Extracellular Vesicles Require β1 Integrins to Promote Anchorage-Independent Growth

et al. 2019

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Summary The β1 integrins, known to promote cancer progression, are abundant in extracellular vesicles (EVs). We investigated whether prostate cancer (PrCa) EVs affect anchorage-independent growth and whether β1 integrins are required for this effect. Specifically using a cell-line-based genetic rescue and an in vivo PrCa model, we show that gradient-purified small EVs (sEVs) from either cancer cells or blood from tumor-bearing TRAMP (transgenic adenocarcinoma of the mouse prostate) mice promote anchorage-independent growth of PrCa cells. In contrast, sEVs from cultured PrCa cells harboring a short hairpin RNA to β1, from wild-type mice or from TRAMP mice carrying a β1 conditional ablation in the prostatic epithelium (β1 pc−/− ), do not. We find that sEVs, from cancer cells or TRAMP blood, are functional and co-express β1 and sEV markers; in contrast, sEVs from β1 pc−/− /TRAMP or wild-type mice lack β1 and sEV markers. Our results demonstrate that β1 integrins in tumor-cell-derived sEVs are required for stimulation of anchorage-independent growth.

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Section: Resultsmentioning

confidence: 99%

Tumor-Derived Extracellular Vesicles Require β1 Integrins to Promote Anchorage-Independent Growth

et al. 2019

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“…Moreover, airway wall remodeling includes epithelial and airway smooth muscle (ASM) cell proliferation, and neovascularisation, which might be upregulated by ECM components, particularly fibronectin [15][16][17]. Recently, Sundaram et al [18] have shown that a specific blockade of α 5 β 1 integrin, a primary fibronectin-binding receptor in ASM, is related to the inhibition of contraction in murine and human ASM.…”

Section: Introductionmentioning

confidence: 99%

Increased blood levels of cellular fibronectin in asthma: Relation to the asthma severity, inflammation, and prothrombotic blood alterations

Bazan-Socha

Kuczia

Potaczek

et al. 2018

Respiratory Medicine

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“…By using integrin blocking antibodies, we further determined that degradation of I27-tension probes was dependent on α 5 β 1 integrin signaling (Figure S5C, Supporting Information). [30] Further evidence of protease release is revealed by the pre-treatment of ASM cells with doxycycline (4 μg/ml, 24 h), a known inhibitor of MMP expression [31] (Figure S5D, Supporting Information). Inhibiting MMP expression led to a marked increase in Cy3 tension signal and the absence of dark signal at the cell perimeter.…”

Section: Resultsmentioning

confidence: 99%

Molecular Tension Probes to Investigate the Mechanopharmacology of Single Cells: A Step toward Personalized Mechanomedicine

Galior

Pui‐Yan

Liu

et al. 2018

Adv Healthcare Materials

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Given that dysregulation of mechanics contributes to diseases ranging from cancer metastasis to lung disease, it is important to develop methods for screening the efficacy of drugs that target cellular forces. Here, nanoparticle-based tension sensors are used to quantify the mechanical response of individual cells upon drug treatment. As a proof-of-concept, the activity of bronchodilators is tested on human airway smooth muscle cells derived from seven donors, four of which are asthmatic. It is revealed that airway smooth muscle cells isolated from asthmatic donors exhibit greater traction forces compared to the control donors. Additionally, the mechanical signal is abolished using myosin inhibitors or further enhanced in the presence of inflammatory inducers, such as nicotine. Using the signal generated by the probes, single-cell dose-response measurements are performed to determine the "mechano" effective concentration (mechano-EC ) of albuterol, a bronchodilator, which reduces integrin forces by 50%. Mechano-EC values for each donor present discrete readings that are differentially enhanced as a function of nicotine treatment. Importantly, donor mechano-EC values varied by orders of magnitude, suggesting significant variability in their sensitivity to nicotine and albuterol treatment. To the best of the authors' knowledge, this is the first study harnessing a piconewton tension sensor platform for mechanopharmacology.

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Targeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthma

Cited by 24 publications

References 48 publications

Tumor-Derived Extracellular Vesicles Require β1 Integrins to Promote Anchorage-Independent Growth

Tumor-Derived Extracellular Vesicles Require β1 Integrins to Promote Anchorage-Independent Growth

Increased blood levels of cellular fibronectin in asthma: Relation to the asthma severity, inflammation, and prothrombotic blood alterations

Molecular Tension Probes to Investigate the Mechanopharmacology of Single Cells: A Step toward Personalized Mechanomedicine

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