Integrin beta 1 inhibition alleviates the chronic hyperproliferative dermatitis phenotype of SHARPIN-deficient mice

Peuhu, Emilia; Salomaa, Siiri I.; Franceschi, Nicola De; Potter, Christopher S.; Sundberg, John P.; Pouwels, Jeroen

doi:10.1371/journal.pone.0186628

Cited by 16 publications

(17 citation statements)

References 36 publications

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“…Thus, a higher proportion of cell-surface integrins appear to be in an active state in the absence of SHARPIN ( Fig. 2B), in line with our previous studies with MSFs (Peuhu, Kaukonen et al, 2017) and other cell types (Peuhu, Salomaa et al, 2017, Rantala et al, 2011. Next, we analyzed the cell-surface protein levels of integrin β1-binding α-subunits and found that Sharpin cpdm MSFs had slightly downregulated levels of integrin α5, but significantly reduced levels of integrins α1 and α11 on the cell surface compared to wild-type MSFs (Fig.…”

Section: Integrin α111 Protein Levels Regulate the Spreading Of Msfssupporting

confidence: 91%

“…While the role of integrins as cell mechanosensors and transducers is well established, the link between the regulation of integrin activity and the mechanosensing response on different ECM ligands remains poorly understood. SHARPIN is a cytosolic adaptor protein that, among other functions, binds to the intracellular integrin alpha tails and inhibits integrin activity in vitro and in vivo (Peuhu, Kaukonen et al, 2017, Peuhu, Salomaa et al, 2017, Pouwels et al, 2013, Rantala et al, 2011. We have previously demonstrated that stromal SHARPIN deficiency interferes with normal mouse mammary gland development and collagen fiber assembly in vivo (Peuhu, Kaukonen et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts

Lerche

Elosegui‐Artola

Guzmán

et al. 2019

Preprint

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The link between the modulation of integrin activity and cellular mechanosensing of tissue rigidity, especially on different extracellular matrix ligands, remains poorly understood. Here, we find that primary mouse mammary gland stromal fibroblasts (MSFs) are mechanically distinct from previously studied cell types. In particular, MSFs generate high forces at a low matrix stiffness, equivalent to the soft mammary gland tissue, supported by maximal focal adhesion maturation, strong actin stress fiber formation, and myosin phosphorylation.We describe that loss of the cytosolic integrin inhibitor, SHARPIN, triggers impeded spreading of MSFs specifically on soft type I collagen but not on fibronectin. Through quantitative experiments and computational modelling, we find that reduced expression of the collagen-binding integrin α11β1 in SHARPIN-deficient MSFs leads to faster force-induced unbinding of adhesions from collagen. Faster unbinding, in turn, impairs force transmission in these cells, particularly, at the stiffness optimum observed for wild-type cells, and increases actin retrograde flow. Our results unveil a collagen-specific mechanosensing mechanism and suggest a key function for integrin activity regulation and integrin α11β1 in MSF mechanotransduction.

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Section: Integrin α111 Protein Levels Regulate the Spreading Of Msfssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts

Lerche

Elosegui‐Artola

Guzmán

et al. 2019

Preprint

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“…Nonlabeled DOTA-E[c(RGDfK)] 2 peptide and 68 Ga-DOTA-E[c(RGEfK)] 2 peptide significantly reduced the tracer uptake in, for example, small intestine, thus indicating higher level of specific a v b 3 binding in Sharpin cpdm mice than in the wt littermates. In competition experiments, we did not see reduced uptake in the skin of Sharpin cpdm mice, most likely because the skin phenotype is more b 1 integrin-dependent (15). a v b 3 integrin is overexpressed on angiogenic endothelial cells and is a well-validated target for assessing tumor angiogenesis (1).…”

Section: Discussionmentioning

confidence: 98%

“…1A). In these mice, increased integrin activity has been detected in the skin, leukocytes, and mammary gland stromal fibroblasts (12,(15)(16)(17). Although integrins are known to play an important role in tumor growth, invasion, angiogenesis, and metastasis (1), it is currently unclear how regulation of integrin activity in the tumor microenvironment influences these processes.…”

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confidence: 99%

⁶⁸Ga-DOTA-E[c(RGDfK)]₂ PET Imaging of SHARPIN-Regulated Integrin Activity in Mice

et al. 2019

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Shank-associated RH domain-interacting protein (SHARPIN) is a cytosolic protein that plays a key role in activation of nuclear factor κ-light-chain enhancer of activated B cells and regulation of inflammation. Furthermore, SHARPIN controls integrin-dependent cell adhesion and migration in several normal and malignant cell types, and loss of SHARPIN correlates with increased integrin activity in mice. Arginyl-glycyl-aspartic acid (RGD), a cell adhesion tripeptide motif, is an integrin recognition sequence that facilitates PET imaging of integrin upregulation during tumor angiogenesis. We hypothesized that increased integrin activity due to loss of SHARPIN protein would affect the uptake of α v β 3-selective cyclic, dimeric peptide 68 Ga-DOTA-E[c(RGDfK)] 2 , where E[c(RGDfk)] 2 5 glutamic acid-[cyclo(arginyl-glycylaspartic acid-D-phenylalanine-lysine)], both in several tissue types and in the tumor microenvironment. To test this hypothesis, we used RGDbased in vivo PET imaging to evaluate wild-type (wt) and SHARPIN-deficient mice (Sharpin cpdm , where cpdm 5 chronic proliferative dermatitis in mice) with and without melanoma tumor allografts. Methods: Sharpin cpdm mice with spontaneous null mutation in the Sharpin gene and their wt littermates with or without B16-F10-luc melanoma tumors were studied by in vivo imaging and ex vivo measurements with cyclic-RGD peptide 68 Ga-DOTA-E[c(RGDfK)] 2. After the last 68 Ga-DOTA-E[c(RGDfK)] 2 peptide PET/CT, tumors were cut into cryosections for autoradiography, histology, and immunohistochemistry. Results: The ex vivo uptake of 68 Ga-DOTA-E[c(RGDfK)] 2 in the mouse skin and tumor was significantly higher in Sharpin cpdm mice than in wt mice. B16-F10-luc tumors were detected 4 d after inoculation, without differences in volume or blood flow between the mouse strains. PET imaging with 68 Ga-DOTA-E[c(RGDfK)] 2 peptide at day 10 after inoculation revealed significantly higher uptake in the tumors transplanted into Sharpin cpdm mice than in wt mice. Furthermore, tumor vascularization was increased in the Sharpin cpdm mice. Conclusion: Sharpin cpdm mice demonstrated increased integrin activity and vascularization in B16-F10-luc melanoma tumors, as demonstrated by RGD-based in vivo PET imaging. These data indicate that SHARPIN, a protein previously associated with increased cancer growth and metastasis, may also have important regulatory roles in controlling the tumor microenvironment.

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“…SHANK-associated RH domain interacting protein (SHARPIN) is a ubiquitin-related protein involved in several processes, including inflammatory responses, the development of both normal and cancer tissues [ 69 ], and inhibition of integrin activity in different cell types [ 70 , 71 , 72 , 73 ]. Under physiological conditions, stromal SHARPIN regulates ductal outgrowth during puberty [ 32 ].…”

Section: Mammary Gland Structure and Developmentmentioning

confidence: 99%

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

Avagliano

Fiume

Ruocco

et al. 2020

Cancers

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The stromal microenvironment regulates mammary gland development and tumorigenesis. In normal mammary glands, the stromal microenvironment encompasses the ducts and contains fibroblasts, the main regulators of branching morphogenesis. Understanding the way fibroblast signaling pathways regulate mammary gland development may offer insights into the mechanisms of breast cancer (BC) biology. In fact, the unregulated mammary fibroblast signaling pathways, associated with alterations in extracellular matrix (ECM) remodeling and branching morphogenesis, drive breast cancer microenvironment (BCM) remodeling and cancer growth. The BCM comprises a very heterogeneous tissue containing non-cancer stromal cells, namely, breast cancer-associated fibroblasts (BCAFs), which represent most of the tumor mass. Moreover, the different components of the BCM highly interact with cancer cells, thereby generating a tightly intertwined network. In particular, BC cells activate recruited normal fibroblasts in BCAFs, which, in turn, promote BCM remodeling and metastasis. Thus, comparing the roles of normal fibroblasts and BCAFs in the physiological and metastatic processes, could provide a deeper understanding of the signaling pathways regulating BC dissemination. Here, we review the latest literature describing the structure of the mammary gland and the BCM and summarize the influence of epithelial-mesenchymal transition (EpMT) and autophagy in BC dissemination. Finally, we discuss the roles of fibroblasts and BCAFs in mammary gland development and BCM remodeling, respectively.

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Integrin beta 1 inhibition alleviates the chronic hyperproliferative dermatitis phenotype of SHARPIN-deficient mice

Cited by 16 publications

References 36 publications

Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts

Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts

⁶⁸Ga-DOTA-E[c(RGDfK)]₂ PET Imaging of SHARPIN-Regulated Integrin Activity in Mice

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

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Integrin beta 1 inhibition alleviates the chronic hyperproliferative dermatitis phenotype of SHARPIN-deficient mice

Cited by 16 publications

References 36 publications

Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts

Integrin binding dynamics modulate ligand-specific mechanosensing in mammary gland fibroblasts

68Ga-DOTA-E[c(RGDfK)]2 PET Imaging of SHARPIN-Regulated Integrin Activity in Mice

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

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⁶⁸Ga-DOTA-E[c(RGDfK)]₂ PET Imaging of SHARPIN-Regulated Integrin Activity in Mice