Focal-adhesion-independent integrin-αv regulation of FAK and c-Myc is necessary for 3D skin formation and tumor invasion

Duperret, Elizabeth K.; Dahal, Ankit; Ridky, Todd W.

doi:10.1242/jcs.175539

Cited by 52 publications

(58 citation statements)

References 86 publications

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“…To establish these tissues, primary keratinocytes were seeded into a native human dermal matrix, and allowed to proliferate and stratify for 10 days at the air-liquid interface. 6,[28][29][30] We have previously used this approach to show that human keratinocytes require integrin av to maintain the capacity to both proliferate in culture, and to regenerate stratified epidermis. 6 However, inducible genetic av depletion in established mature epidermis has no obvious deleterious effect.…”

Section: Results Av Integrins Are Necessary For Organotypic Wound Reementioning

confidence: 99%

“…6,[28][29][30] We have previously used this approach to show that human keratinocytes require integrin av to maintain the capacity to both proliferate in culture, and to regenerate stratified epidermis. 6 However, inducible genetic av depletion in established mature epidermis has no obvious deleterious effect. 6 This suggested that av may be required for wound reepithelialization, but may be dispensable for normal epidermal tissue maintenance.…”

Section: Results Av Integrins Are Necessary For Organotypic Wound Reementioning

confidence: 99%

“…6 However, inducible genetic av depletion in established mature epidermis has no obvious deleterious effect. 6 This suggested that av may be required for wound reepithelialization, but may be dispensable for normal epidermal tissue maintenance. To test this idea, we first used a complementary antibody-mediated approach to antagonize integrin av activity.…”

Section: Results Av Integrins Are Necessary For Organotypic Wound Reementioning

confidence: 99%

“…There are 16 different a subunits and 8 different b subunits, which together form 24 ab heterodimersmany of which are expressed in human keratinocytes. 6 One of these heterodimers, a9b1, is essential for keratinocyte re-epithelialization during wound healing, while another, a3b1, inhibits keratinocyte migration during wound healing. 7,8 The av class of integrins (specifically, avb6) and their ligands-vitronectin, fibronectin, TGFb, thrombospondin and osteopontin-are upregulated during wound healing in humans.…”

Section: Introductionmentioning

confidence: 99%

“…[20][21][22][23][24] We previously showed that integrin av is necessary for keratinocyte proliferation in organotypic skin, and thus we hypothesized that av integrins are essential for wound re-epithelialization. 6 Here, we develop a novel, human organotypic wound re-epithelialization assay and show, both in vivo and in vitro, that av integrin function in keratinocytes is required for keratinocyte proliferation and efficient wound reepithelialization. In in vivo xenograft wounds, human skin tissue does not contract rapidly upon wounding, as it does in mouse skin, and thus re-epithelialization can be directly visualized over time.…”

Section: Introductionmentioning

confidence: 99%

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The integrin αv-TGFβ signaling axis is necessary for epidermal proliferation during cutaneous wound healing

et al. 2016

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Proliferation and migration of epidermal keratinocytes are essential for proper cutaneous wound closure after injury. av integrins and several of their ligands-vitronectin, TGFb and thrombospondin-are upregulated in healing wounds. However, the role of av integrins in wound re-epithelialization is unknown. Here, we show that genetic depletion or antibody-mediated blockade of pan-integrin av, or the specific heterodimer avb6, in keratinocytes limited epidermal proliferation at the wound edge and prevented reepithelialization of wounded human organotypic skin both in vivo and in vitro. While we did not observe a migration defect upon av blockade in vivo, av was necessary for keratinocyte migration over longer distances in organotypic skin. Integrin av is required for local activation of latent TGFb, and the wound healing defect in the setting of integrin av loss was rescued by exogenous, active TGFb, indicating that the av-TGFb signaling axis is a critical component of the normal epidermal wound healing program. As chronic wounds are associated with decreased TGFb signaling, restoration of TGFb activity may have therapeutic utility in some clinical settings.

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Section: Results Av Integrins Are Necessary For Organotypic Wound Reementioning

confidence: 99%

Section: Results Av Integrins Are Necessary For Organotypic Wound Reementioning

confidence: 99%

Section: Results Av Integrins Are Necessary For Organotypic Wound Reementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The integrin αv-TGFβ signaling axis is necessary for epidermal proliferation during cutaneous wound healing

et al. 2016

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Focal adhesion kinase activation limits efficacy of Dasatinib in c‐Myc driven hepatocellular carcinoma

et al. 2018

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Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. Recently, it was found that Dasatinib treatment led to synthetic lethality in c‐Myc high‐expressing human cancer cells due to inhibition of p‐Lyn. Overexpression of c‐Myc is frequently seen in human HCC. We investigated the sensitivity to Dasatinib in vitro using HCC cell lines and in vivo using c‐Myc mouse HCC model. We found that HCC cell line responsiveness to Dasatinib varied significantly. However, there was no correlation between c‐Myc expression and IC 50 to Dasatinib. In c‐Myc‐induced HCC in mice, tumors continued to grow despite Dasatinib treatment, although the eventual tumor burden was lower in Dasatinib treatment cohort. Molecular analyses revealed that Dasatinib was effective in inhibiting p‐Src, but not p‐Lyn, in HCC. Importantly, we found that in HCC cell lines as well as c‐Myc mouse HCC, Dasatinib treatment induced up regulation of activated/phosphorylated (p)‐focal adhesion kinase(FAK). Concomitant treatment of HCC cell lines with Dasatinib and FAK inhibitor prevented Dasatinib‐induced FAK activation, leading to stronger growth restraint. Altogether, our results suggest that Dasatinib may have limited efficacy as single agent for HCC treatment. Combined treatment with Dasatinib with FAK inhibitor might represent a novel therapeutic approach against HCC.

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Exostosin1 as a novel prognostic and predictive biomarker for squamous cell lung carcinoma: A study based on bioinformatics analysis

Huo

Jiang

et al. 2020

Cancer Medicine

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The exostosin (EXT) protein family is involved in diverse human diseases. However, the expression and prognostic value of EXT genes in human lung squamous cell carcinoma (LUSC) is not well understood. In this study, we analyzed the association between expression of EXT1 and EXT2 genes and survival in patients with LUSC using bioinformatics resources such as Oncomine and The Cancer Genome Atlas (TCGA) databases, the Gene Expression Profiling Interactive Analysis (GEPIA) server and Kaplan–Meier plotter. Furthermore, regulatory microRNAs (miRNAs) were predicted for EXT1 and used to establish a potential miRNA‐messenger RNA (mRNA) regulation network for LUSC using the ENCORI platform. We observed that EXT1 and EXT2 expression levels were higher in LUSC than those in normal tissues. However, only EXT1 expression was significantly associated with poor overall survival (OS) in LUSC patients. Functional annotation enrichment analysis showed that genes co‐expressed with the EXT1 gene were enriched in biological processes such as cell adhesion and migration, and KEGG pathways such as extracellular matrix receptor interactions, complement and coagulation cascades, and cell death. Furthermore, three miRNAs, hsa‐mir‐190a‐5p, hsa‐mir‐195‐5p, and hsa‐mir‐490‐3p, were identified to be potentially involved in the regulation of EXT1. In summary, we identified EXT1 expression as a novel potential prognostic marker for human LUSC and the regulatory miRNAs that could possibly contribute to the prognosis of the disease.

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Focal-adhesion-independent integrin-αv regulation of FAK and c-Myc is necessary for 3D skin formation and tumor invasion

Cited by 52 publications

References 86 publications

The integrin αv-TGFβ signaling axis is necessary for epidermal proliferation during cutaneous wound healing

The integrin αv-TGFβ signaling axis is necessary for epidermal proliferation during cutaneous wound healing

Focal adhesion kinase activation limits efficacy of Dasatinib in c‐Myc driven hepatocellular carcinoma

Exostosin1 as a novel prognostic and predictive biomarker for squamous cell lung carcinoma: A study based on bioinformatics analysis

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