scholarly journals Cholesterol deprivation induces TGFβ signaling to promote basal differentiation in pancreatic cancer

2019 ◽  
Author(s):  
Linara G. Cornell ◽  
Suraj Peri ◽  
Diana Restifo ◽  
Alena Klochkova ◽  
Tiffiney R. Hartman ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Ductal Adenocarcinoma ◽  
Tgfβ Signaling ◽  
Pancreatic Development ◽  
Mesenchymal Phenotype ◽  
Tgfβ Receptor ◽  
Growth Factor Beta

SummaryOncogenic transformation alters the metabolism of cellular nutrients to sustain tumor growth. We here define a mechanism by which modifications in cholesterol metabolism control the formation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by means of conditional inactivation ofNsdhlin mice bearing a tumor-inducingKrasmutation (KrasG12D) prevented PDAC formation in the context of a heterozygousTrp53f/+genotype without impairing normal pancreatic development. In mice with pancreaticNsdhlablation and homozygous loss ofTrp53, the emerging tumors presented with the aggressive basal (mesenchymal) phenotype as opposed to the classic (glandular) PDAC. This paralleled significantly reduced expression of cholesterol metabolic pathway genes in human basal PDAC subtype. Mechanistically, we demonstrate that genetic or metabolic cholesterol deprivation stabilizes the transforming growth factor beta (TGFβ) receptor to activate pro-mesenchymal effectors in human and murine PDAC, providing a direct mechanism by which cholesterol metabolism can condition tumor differentiation.

Abstract 248: Aberrant TGFβ Signaling as an Etiology of Left Ventricular Non-compaction Cardiomyopathy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kazuki Kodo ◽  
Sang-Ging Ong ◽  
Fereshteh Jahanbani ◽  
Vittavat Termglinchan ◽  
Kolsoum InanlooRahatloo ◽  
...  
Keyword(s):  
Left Ventricle ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Induced Pluripotent Stem Cell ◽  
Left Ventricular ◽  
Patient Specific ◽  
Developmental Defect ◽  
Tgfβ Signaling ◽  
Growth Factor Beta ◽  
Induced Pluripotent

Left ventricular non-compaction (LVNC) is the third most prevalent cardiomyopathy in children and has a unique phenotype with characteristically extensive hypertrabeculation of the left ventricle, similar to the embryonic left ventricle, suggesting a developmental defect of the embryonic myocardium. However, studying this disease has been challenging due to the lack of an animal model that can faithfully recapitulate the clinical phenotype of LVNC. To address this, we showed that patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from a family with LVNC history recapitulated a developmental defect consistent with the LVNC phenotype at the single-cell level. We then utilized hiPSC-CMs to show that increased transforming growth factor beta (TGFβ) signaling is one of the central mechanisms underlying the pathogenesis of LVNC. LVNC hiPSC-CMs demonstrated decreased proliferative capacity due to abnormal activation of TGFβ signaling (Figs A-B). Exome sequencing demonstrated a mutation in TBX20, which regulates TGFβ signaling through upregulation of ITGAV, contributing to the LVNC phenotype. Inhibition of abnormal TGFβ signaling or genetic correction of the TBX20 mutation (Figs C-D) using TALEN reversed the proliferation defects seen in LVNC hiPSC-CMs. Our results demonstrate that hiPSC-CMs are a useful tool for the exploration of novel mechanisms underlying poorly understood cardiomyopathies such as LVNC. Here we provide the first evidence of activation of TGFβ signaling as playing a role in the pathogenesis of LVNC.

scholarly journals Transforming growth factor beta (TGFβ) signaling is regulated at the pocket region of primary cilia

Cilia ◽  
2012 ◽  
Vol 1 (S1) ◽  
Author(s):  
S Christensen ◽  
CA Clement ◽  
SK Brorsen ◽  
KD Ajbro ◽  
M de Jesus ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Primary Cilia ◽  
Transforming Growth Factor ◽  
Tgfβ Signaling ◽  
Growth Factor Beta

scholarly journals TGFβ (Transforming Growth Factor-Beta)–Activated Kinase 1 Regulates Arteriovenous Fistula Maturation

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Haidi Hu ◽  
Shin-Rong Lee ◽  
Hualong Bai ◽  
Jianming Guo ◽  
Takuya Hashimoto ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Wall Thickening ◽  
Laminar Shear Stress ◽  
Tgfβ Signaling ◽  
Luminal Diameter ◽  
Ecm Extracellular Matrix ◽  
Growth Factor Beta

Objective: Arteriovenous fistulae (AVF) are the optimal conduit for hemodialysis access but have high rates of primary maturation failure. Successful AVF maturation requires wall thickening with deposition of ECM (extracellular matrix) including collagen and fibronectin, as well as lumen dilation. TAK1 (TGFβ [transforming growth factor-beta]–activated kinase 1) is a mediator of noncanonical TGFβ signaling and plays crucial roles in regulation of ECM production and deposition; therefore, we hypothesized that TAK1 regulates wall thickening and lumen dilation during AVF maturation. Approach and Results: In both human and mouse AVF, immunoreactivity of TAK1, JNK (c-Jun N-terminal kinase), p38, collagen 1, and fibronectin was significantly increased compared with control veins. Manipulation of TAK1 in vivo altered AVF wall thickening and luminal diameter; reduced TAK1 function was associated with reduced thickness and smaller diameter, whereas activation of TAK1 function was associated with increased thickness and larger diameter. Arterial magnitudes of laminar shear stress (20 dyne/cm 2 ) activated noncanonical TGFβ signaling including TAK1 phosphorylation in mouse endothelial cells. Conclusions: TAK1 is increased in AVF, and TAK1 manipulation in a mouse AVF model regulates AVF thickness and diameter. Targeting noncanonical TGFβ signaling such as TAK1 might be a novel therapeutic approach to improve AVF maturation.

scholarly journals Transforming growth factor beta signaling and decidual integrity in mice†

2020 ◽  
Vol 103 (6) ◽  
pp. 1186-1198
Author(s):  
Xin Fang ◽  
Nan Ni ◽  
Yang Gao ◽  
John P Lydon ◽  
Ivan Ivanov ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Female Reproductive Tract ◽  
Molecular Properties ◽  
Conditional Knockout ◽  
Decidual Cell ◽  
Tgfβ Signaling ◽  
Growth Factor Beta

Abstract Transforming growth factor beta (TGFβ) signaling regulates multifaceted reproductive processes. It has been shown that the type 1 receptor of TGFβ (TGFBR1) is indispensable for female reproductive tract development, implantation, placental development, and fertility. However, the role of TGFβ signaling in decidual development and function remains poorly defined. Our objective is to determine the impact of uterine-specific deletion of Tgfbr1 on decidual integrity, with a focus on the cellular and molecular properties of the decidua during development. Our results show that the developmental dynamics of the decidua is altered in TGFBR1 conditionally depleted uteri from embryonic day (E) 5.5 to E8.5, substantiated by downregulation of genes associated with inflammatory responses and uterine natural killer cell abundance, reduced presence of nondecidualized fibroblasts in the antimesometrial region, and altered decidual cell development. Notably, conditional ablation of TGFBR1 results in the formation of decidua containing more abundant alpha smooth muscle actin (ACTA2)-positive cells at the peripheral region of the antimesometrial side versus controls at E6.5–E8.5. This finding is corroborated by upregulation of a subset of smooth muscle marker genes in Tgfbr1 conditionally deleted decidua at E6.5 and E8.5. Moreover, increased cell proliferation and enhanced decidual ERK1/2 signaling were found in Tgfbr1 conditional knockout mice upon decidual regression. In summary, conditional ablation of TGFBR1 in the uterus profoundly impacts the cellular and molecular properties of the decidua. Our results suggest that TGFBR1 in uterine epithelial and stromal compartments is important for the integrity of the decidua, a transient but crucial structure that supports embryo development.

scholarly journals Cooperation between Snail and LEF-1 Transcription Factors Is Essential for TGF-β1-induced Epithelial-Mesenchymal Transition

2006 ◽  
Vol 17 (4) ◽  
pp. 1871-1879 ◽  
Author(s):  
Damian Medici ◽  
Elizabeth D. Hay ◽  
Daniel A. Goodenough
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Mdckii Cells ◽  
Growth Factor Beta ◽  
Tgf Β1 ◽  
Expression Loss ◽  
E Cadherin

Transforming growth factor beta 1 (TGF-β1) has been shown to induce epithelial-mesenchymal transition (EMT) during various stages of embryogenesis and progressive disease. This alteration in cellular morphology is typically characterized by changes in cell polarity and loss of adhesion proteins such as E-cadherin. Here we demonstrate that EMT is associated with loss of claudin-1, claudin-2, occludin, and E-cadherin expression within 72 h of exposure to TGF-β1 in MDCKII cells. It has been suggested that this expression loss occurs through TGF-β1 in a Smad-independent mechanism, involving MEK and PI3K pathways, which have previously been shown to induce expression of the Snail (SNAI-1) gene. Here we show that these pathways are responsible for loss of tight junctions and a partial loss of E-cadherin. However, our results also demonstrate that a complete loss of E-cadherin and transformation to the mesenchymal phenotype are dependent on Smad signaling, which subsequently stimulates formation of β-catenin/LEF-1 complexes that induce EMT.

scholarly journals TGFBR2 mutation predicts resistance to immune checkpoint inhibitors in patients with non-small cell lung cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592110384
Author(s):  
Teng Li ◽  
Han Wang ◽  
Jiachen Xu ◽  
Chengcheng Li ◽  
Yudong Zhang ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Transforming Growth Factor ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung ◽  
Tgfβ Receptor ◽  
Growth Factor Beta

Background: Resistance or even hyper-progression to immune checkpoint inhibitors (ICIs) manifesting as accelerated disease progression or death has impeded the clinical use of ICIs. The transforming growth factor beta (TGFβ) receptor pathway has been identified in contributing to immune dysfunction, which might be associated with resistance to ICIs. We aimed to explore the role of TGFβ in the resistance to ICIs in non-small cell lung cancer (NSCLC) in this study. Methods: Public cohorts with patients treated with ICIs or chemotherapy including POPLAR/OAK ( n = 853), MSKCC ( n = 1662) and Van Allen ( n = 57) and TCGA ( n = 3210) cohorts were obtained and analyzed. Results: The expression of immune-checkpoint related genes, including programmed death-ligand 1 ( CD274), lymphocyte-activation gene 3 ( LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T-lymphocyte-associated protein 4 ( CTLA-4), programmed cell death ligand 1 ( PDCD1), and programmed cell death 1 ligand 2 ( PDCD1LG2) were significantly upregulated in transforming growth factor beta TGFβ receptor 2 (TGFβR2)-mutated patients than those with wild-type TGFBR2 ( p < 0.05). In the POPLAR/OAK cohort, TGFBR2-mutated patients showed shorter progression-free survival (PFS) [ p = 0.004; hazard ratio (HR), 2.83; 95% confidence interval (CI), 1.34–6.00] and overall survival (OS) ( p = 0.0006; HR, 3.46; 95% CI, 1.63–7.35) than those with wild-type TGFBR2 when treated with ICIs but not chemotherapy. In the merged MSKCC and Van Allen cohorts, a similar result was observed that the OS was inferior in patients with mutated TGFBR2 compared with those with wild-type TGFBR2 ( p = 0.007; HR, 2.53; 95% CI, 1.25–5.12). The association between TGBFR2 mutation and survival remained significant in multivariable cox regression in both POPLAR/OAK cohort ( p = 0.02; HR, 2.53; 95% CI, 1.17–5.45) and merged cohort ( p = 0.008; HR, 2.63; 95% CI, 1.29–5.35). We further evaluated the association between TGFBR2 mutations and OS in multiple types of tumors. The association between TGFBR2 mutations and OS remained significant in NSCLC ( p = 0.02; HR, 2.47; 95% CI, 1.16–5.26), but not in other type of tumors. Conclusions: We identified that TGFBR2 mutation predicted the resistance to ICIs in NSCLCs. The clinical delivery of ICIs should be cautious in those patients.

scholarly journals A Complex Case of Loeys-Dietz Syndrome: A Case Report and Review of the Literature

2016 ◽  
Vol 6 (4) ◽  
pp. 731-738
Author(s):  
Tiffany N. Caza ◽  
Ana Mercedes ◽  
Robert Stoppacher ◽  
Charles A. Catanese
Keyword(s):  
Transforming Growth Factor Beta ◽  
Autosomal Dominant ◽  
Transforming Growth Factor ◽  
Clinical Presentation ◽  
Genetic Mutation ◽  
Connective Tissue Disorder ◽  
Complex Case ◽  
Tgfβ Signaling ◽  
Aneurysm Formation ◽  
Growth Factor Beta

Loeys-Dietz syndrome is a rare autosomal dominant connective tissue disorder with a genetic predisposition to aneurysm formation and congenital cardiofacial defects through genetic mutation affecting the transforming growth factor-beta (TGFβ) signaling pathway. We present a case of a 6-year-old female patient with Loeys-Dietz syndrome who developed an annular aortic valve abscess and ascending aortic dissection due to Staphylococcus aureus endocarditis. Within this case, multiple complications from Loeys-Dietz syndrome were identified, including prosthetic valve infection, aneurysm formation and dissection, septic embolism, and aspiration pneumonia. The clinical presentation, pathologic findings, and pathophysiology will be discussed.

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