Expression of ganglioside GD2, reprogram the lipid metabolism and EMT phenotype in bladder cancer

Vantaku, Venkatrao; Donepudi, Sri Ramya; Ambati, Chandrashekar R.; Jin, Feng; Putluri, Vasanta; Nguyen, Khoa; Rajapakshe, Kimal; Coarfa, Cristian; Battula, Venkata Lokesh; Lotan, Yair; Putluri, Nagireddy

doi:10.18632/oncotarget.21038

Cited by 42 publications

(34 citation statements)

References 57 publications

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“…Urinary ACR was determined using mouse albumin ELISA kit (Molecular Innovations) and QuantiChrom Creatinine Assay Kit (BioAssay Systems), per the manufacturers' protocols. The absolute concentration of serum creatinine was determined by Metabolomics Core, Baylor College of Medicine (57).…”

Section: Discussionmentioning

confidence: 99%

PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease

et al. 2019

Journal of Clinical Investigation

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Epithelial-mesenchymal transition (EMT) contributes significantly to interstitial matrix deposition in diabetic kidney disease (DKD). However, detection of EMT in kidney tissue is impracticable, and anti-EMT therapies have long been hindered. We reported that phosphatase and tensin homolog (PTEN) promoted transforming growth factor beta 1 (TGF-β), sonic hedgehog (SHH), connective tissue growth factor (CTGF), interleukin 6 (IL-6), and hyperglycemia-induced EMT when PTEN was modified by a MEX3C-catalyzed K27-linked polyubiquitination at lysine 80 (referred to as PTEN K27-polyUb). Genetic inhibition of PTEN K27-polyUb alleviated Col4a3 knockout-, folic acid-, and streptozotocin-induced (STZ-induced) kidney injury. Serum and urine PTEN K27-polyUb concentrations were negatively correlated with glomerular filtration rate (GFR) for diabetic patients. Mechanistically, PTEN K27-polyUb facilitated dephosphorylation and protein stabilization of TWIST, SNAI1, and YAP in renal epithelial cells, leading to enhanced EMT. We identified that a small molecule, triptolide, inhibited MEX3C-catalyzed PTEN K27-polyUb and EMT of renal epithelial cells. Treatment with triptolide reduced TWIST, SNAI1, and YAP concurrently and improved kidney health in Col4a3 knockout-, folic acid-injured disease models and STZ-induced, BTBR ob/ob diabetic nephropathy models. Hence, we demonstrated the important role of PTEN K27-polyUb in DKD and a promising therapeutic strategy that inhibited the progression of DKD.

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Section: Discussionmentioning

confidence: 99%

PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease

et al. 2019

Journal of Clinical Investigation

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“…All the bladder cancer specimens were procured by a prior written informed consent under Institututional Review Boardapproved protocols. Metabolites were extracted from bladder cancer tissues, and mouse liver pool was used as a quality control and followed the extraction procedure described previously (8,(12)(13)(14). Briefly, 10 mg of tissue was used for the metabolic extraction.…”

Section: Sample Preparation For Metabolomics and Lipidomicsmentioning

confidence: 99%

“…Lipids were extracted using a modified Bligh-Dyer method (15). The extraction was carried out using 2:2:2 ratio of water: methanol:dichloromethane at room temparature after ISTDs into tissues and quality control pool (12). After homogenization of the…”

Section: Sample Preparation For Metabolomics and Lipidomicsmentioning

confidence: 99%

Multi-omics Integration Analysis Robustly Predicts High-Grade Patient Survival and Identifies CPT1B Effect on Fatty Acid Metabolism in Bladder Cancer

Vantaku

Dong

Ambati

et al. 2019

Clinical Cancer Research

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Purpose: The perturbation of metabolic pathways in high-grade bladder cancer has not been investigated. We aimed to identify a metabolic signature in high-grade bladder cancer by integrating unbiased metabolomics, lipidomics, and transcriptomics to predict patient survival and to discover novel therapeutic targets. Experimental Design: We performed high-resolution liquid chromatography mass spectrometry (LC-MS) and bioinformatic analysis to determine the global metabolome and lipidome in high-grade bladder cancer. We further investigated the effects of impaired metabolic pathways using in vitro and in vivo models. Results: We identified 519 differential metabolites and 19 lipids that were differentially expressed between low-grade and high-grade bladder cancer using the NIST MS metabolomics compendium and lipidblast MS/MS libraries, respectively. Pathway analysis revealed a unique set of biochemical pathways that are highly deregulated in high-grade bladder cancer. Integromics analysis identified a molecular gene signature associated with poor patient survival in bladder cancer. Low expression of CPT1B in high-grade tumors was associated with low FAO and low acyl carnitine levels in high-grade bladder cancer, which were confirmed using tissue microarrays. Ectopic expression of the CPT1B in high-grade bladder cancer cells led to reduced EMT in in vitro, and reduced cell proliferation, EMT, and metastasis in vivo. Conclusions: Our study demonstrates a novel approach for the integration of metabolomics, lipidomics, and transcriptomics data, and identifies a common gene signature associated with poor survival in patients with bladder cancer. Our data also suggest that impairment of FAO due to downregulation of CPT1B plays an important role in the progression toward high-grade bladder cancer and provide potential targets for therapeutic intervention.

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“…38 Further, high GD2 expression was found to correlate with metastatic potential in melanoma, osteosarcoma and bladder cancer and enforced GD2 expression, by overexpression of GD3S, leads to enhanced invasiveness and migratory potential in small cell lung cancer and osteosarcoma. [39][40][41][42][43] Based on the outlined findings, we hypothesized that depletion of GD2 positive cells would impair dissemination and metastasis formation. Moreover, GD2-targeted therapy should be able to eliminate BCSC phenotypic DTCs.…”

Section: Discussionmentioning

confidence: 99%

GD2-targeted chimeric antigen receptor T cells prevent metastasis formation by elimination of breast cancer stem-like cells

et al. 2019

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2020) GD2-targeted chimeric antigen receptor T cells prevent metastasis formation by elimination of breast cancer stem-like cells, OncoImmunology, 9:1, 1683345, ABSTRACT Expression of the disialoganglioside GD2 has been identified as a marker antigen associated with a breast cancer stem-like cell (BCSC) phenotype. Here, we report on the evaluation of GD2 as a BCSCspecific target antigen for immunotherapy. GD2 expression was confirmed at variable degree in a set of breast cancer cell lines, predominantly in triple-negative breast cancer (TNBC). To target GD2, we have generated novel anti-GD2 chimeric antigen receptors (GD2-CAR), based on single-chain variable fragments (scFv) derived from the monoclonal antibody (mAb) ch14.18, also known as dinutuximab beta. Expressed on T cells, GD2-CARs mediated specific GD2-dependent T-cell activation and target cell lysis. In contrast to previously described GD2-CARs, no signs of exhaustion by tonic signaling were found. Importantly, application of GD2-CAR expressing T cells (GD2-CAR-T) in an orthotopic xenograft model of TNBC (MDA-MB-231) halted local tumor progression and completely prevented lung metastasis formation. In line with the BCSC model, GD2 expression was only found in a subpopulation (4-6%) of MDA-MB-231 cells before injection. Significant expansion of GD2-CAR-T in tumor-bearing mice as well as T-cell infiltrates in the primary tumor and the lungs were found, indicating site-specific activation of GD2-CAR-T. Our data strongly support previous findings of GD2 as a BCSC-associated antigen. GD2-targeted immunotherapies have been extensively studied in human. In conclusion, GD2-CAR-T should be considered a promising novel approach for GD2-positive breast cancer, especially to eliminate disseminated tumor cells and prevent metastasis formation. ARTICLE HISTORY

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Expression of ganglioside GD2, reprogram the lipid metabolism and EMT phenotype in bladder cancer

Cited by 42 publications

References 57 publications

PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease

PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease

Multi-omics Integration Analysis Robustly Predicts High-Grade Patient Survival and Identifies CPT1B Effect on Fatty Acid Metabolism in Bladder Cancer

GD2-targeted chimeric antigen receptor T cells prevent metastasis formation by elimination of breast cancer stem-like cells

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