Melanoma is the leading cause of skin cancer-related death. As prognosis patients with melanoma remains problematic, identification new therapeutic targets essential. Matricellular proteins are nonstructural extracellular matrix proteins. They secreted into tumor microenvironment to coordinate behavior among different cell types, yet their contribution underinvestigated. Examples matricellular include those comprising CCN family. The family member, CCN1, highly proangiogenic. Herein, we show...

To determine whether celastrol, an inhibitor of the mechanosensitive transcriptional cofactor yes-associated protein-1 (YAP1), impairs ability TGFβ1 to stimulate fibrogenic activity in human gingival fibroblast cell line. Human fibroblasts were pre-treated with celastrol or DMSO followed by stimulation without (4 ng/ml). We then utilized bulk RNA sequencing (RNAseq), real-time polymerase chain reaction (RT-PCR), Western blot, immunofluorescence, proliferation assays if impaired TGFβ1-induced...

Abstract Background: The insulin-like growth factor-I (IGFI) receptor is a potential target for breast cancer treatment and may be influenced by dietary intake. Methods: Nested, case–control study of 265 postmenopausal survivors; primary tissue was stained to determine IGFI status. Change in carbohydrate intake from baseline year 1 estimated 24-hour recalls. Breast recurrence cases (91) were matched two controls (n = 174) on disease characteristics counter change Weighted conditional...

<p>CCN1 deficient stroma vasculature microct</p>

<p>CCN1 deficient stroma vasculature microct</p>

<p>CCN1 deficient stroma vasculature microct</p>

<p>CCN1 expression by fibroblasts is associated with increased tumor penetration of CD4<sup>+</sup> T cells and resistance to anti-PD1 checkpoint inhibitors. <b>A,</b> Tumors were subjected flow cytometry anti-CD4 anti-CD8 antibodies. Percentage positive CD45-staining are indicated wild type (<i>n</i> = 3, CCN1<sup>f/f</sup>) CCN1-deficient CCN1<sup>−/−</sup>) tumors (Student <i>t</i> test). Primary data the median...

<p>Mice harboring Col1A2-Cre-fibroblast–specific deletion for <i>Ccn1</i> show impaired metastasis of B16F10 melanoma cells to the lung. <b>A–C,</b> Mice were examined after 14 days tumor growth. <b>A,</b> Sections stroma stained with anti-CCN1 antibody (<i>N</i> = 3, representative images are shown), verifying loss CCN1 protein expression in mice deleted fibroblasts. Note staining remains tumor. Scale bar 50 µm. <b>B,</b>...

<p>Multivariate analysis of CAF-specific <i>CCN1</i> score as a prognostic marker for reduced overall survival in GSE78220 (<a href="#bib36" target="_blank">36</a>) patients on anti-PD1 checkpoint inhibitors</p>

<p>CCN1 +/+ stroma vasculature microct</p>

<p>CCN1 +/+ stroma vasculature microct</p>

<p>CCN1-deficient stroma show disorganized collagen fibers. Digital pathology phenotypic quantification (PharmaNest, Inc) fibrosis histologic heat chart (<b>A</b>) where each row represents a principal qFT, at the three levels (collagen deposition, fibers morphometry, and architecture). <b>B,</b> The Ph-FCS recapitulates all qFTs for one sample, quantifies phenotype of its differences between CCN1-deficient (KO; <i>n</i> = 5, mean 1.5, Std dev 0.5)...

<p>Multivariate analysis of CAF-specific <i>CCN1</i> score as a prognostic marker for reduced overall survival in GSE78220 (<a href="#bib36" target="_blank">36</a>) patients on anti-PD1 checkpoint inhibitors</p>

<p><i>CCN1</i> is expressed by a subset of CAFs and correlates with expression angiogenic markers. <b>A,</b><i>CCN1</i> bulk tumor stromal scores. Scatterplot representation score (ESTIMATE algorithm) to <i>CCN1</i> in primary melanoma tumors from TCGA (<i>n</i> = 82). The linear regression line shown blue, the 95% confidence interval as gray area around line. Spearman correlation coefficient corresponding <i>P</i>...

<p>CCN1 +/+ stroma vasculature microct</p>

<p>CCN1 +/+ stroma vasculature microct</p>

<p>CCN1 +/+ stroma vasculature microct</p>

<p>CCN1 expression by fibroblasts is associated with increased tumor penetration of CD4<sup>+</sup> T cells and resistance to anti-PD1 checkpoint inhibitors. <b>A,</b> Tumors were subjected flow cytometry anti-CD4 anti-CD8 antibodies. Percentage positive CD45-staining are indicated wild type (<i>n</i> = 3, CCN1<sup>f/f</sup>) CCN1-deficient CCN1<sup>−/−</sup>) tumors (Student <i>t</i> test). Primary data the median...

<p>Deletion of <i>Ccn1</i> in Col1A2-Cre-fibroblasts reduces tumor vasculature. <b>A,</b> Tumors wild-type or mice deleted for were perfused with a CT-contrast agent, as described Materials and Methods. Volume (mL) occupied by vasculature was calculated. Mice lacking their fibroblasts had significantly reduced vascular volume (<i>t</i> test, <i>n</i> = 3, <i>P</i> < 0.05). <b>B,</b> associated stroma stained...

<p>CCN1 deficient stroma vasculature microct</p>

<p>Mice harboring Col1A2-Cre-fibroblast–specific deletion for <i>Ccn1</i> show impaired metastasis of B16F10 melanoma cells to the lung. <b>A–C,</b> Mice were examined after 14 days tumor growth. <b>A,</b> Sections stroma stained with anti-CCN1 antibody (<i>N</i> = 3, representative images are shown), verifying loss CCN1 protein expression in mice deleted fibroblasts. Note staining remains tumor. Scale bar 50 µm. <b>B,</b>...

<div>Abstract<p>Melanoma is the leading cause of skin cancer–related death. As prognosis patients with melanoma remains problematic, identification new therapeutic targets essential. Matricellular proteins are nonstructural extracellular matrix proteins. They secreted into tumor microenvironment to coordinate behavior among different cell types, yet their contribution underinvestigated. Examples matricellular include those comprising CCN family. The family member, CCN1, highly...

<p>CCN1 deficient stroma vasculature microct</p>

<p>In a syngeneic model of metastasis, CCN1-deficient stroma possesses reduced collagen deposition, whereas myofibroblast formation is unaffected. Skin tissue showed significant decrease in shown trichrome and Sirius red staining (<b>A</b>; arrow indicates stroma). Representative images shown; Graph shows mean area collagen, detected using stain, present ± SD; Student <i>t</i> test; <i>n</i> = 3). α-SMA–expressing myofibroblasts...

<p>In a syngeneic model of metastasis, CCN1-deficient stroma possesses reduced collagen deposition, whereas myofibroblast formation is unaffected. Skin tissue showed significant decrease in shown trichrome and Sirius red staining (<b>A</b>; arrow indicates stroma). Representative images shown; Graph shows mean area collagen, detected using stain, present ± SD; Student <i>t</i> test; <i>n</i> = 3). α-SMA–expressing myofibroblasts...