CTGF/VEGFA-activated Fibroblasts Promote Tumor Migration Through Micro-environmental Modulation

Wu, Wei; Zaal, Esther A.; Berkers, Celia R.; Lemeer, Simone; Heck, Albert J. R.

doi:10.1074/mcp.ra118.000708

Cited by 13 publications

(15 citation statements)

References 50 publications

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“…CTGF/CCN2 plays a vital role in tumor-stromal interaction and desmoplasia in PDAC (20,(43)(44)(45). Recent studies have shown that tumor cell-derived CTGF is a prerequisite signal for fibroblast activation (56). Because our current studies found that CTGF expression in pancreatic cancer cells and fibroblast cells is regulated by CYR61/CCN5 ( Fig.…”

Section: Maity Et Almentioning

confidence: 48%

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma

Maity

Ghosh

Gupta

et al. 2019

Molecular Cancer Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) develops extrinsic-and intrinsic-resistant phenotypes to prevent chemotherapies from entering into the cells by promoting desmoplastic reactions (DR) and metabolic malfunctions of the drugs. It is well established that these responses are also associated with pancreatic cancer cells' gemcitabine resistance. However, the mechanism by which these resistant pathways function in the pancreatic cancer cells remains poorly understood. In these studies, we show that CYR61/ CCN1 signaling plays a vital role in making pancreatic cancer cells resistant to gemcitabine in vitro and also in a tumor xenograft model. We proved that the catastrophic effect of gemcitabine could significantly be increased in gemcitabineresistant PDAC cells when CYR61/CCN1 is depleted, while this effect can be suppressed in gemcitabine-sensitive neoplastic cells by treating them with CYR61/CCN1 recombinant protein. Ironically, nontransformed pancreatic cells, which are sensitive to gemcitabine, cannot be resistant to gemcitabine by CYR61/CCN1 protein treatment, showing a unique feature of CYR61/CCN signaling that only influences PDAC cells to become resistant. Furthermore, we demonstrated that CYR61/CCN1 suppresses the expression of the gemcitabineactivating enzyme deoxycytidine kinase (dCK) while it induces the expression of a DR-promoting factor CTGF (connective tissue growth factor) in pancreatic cancer cells in vitro and in vivo. Thus, the previously described mechanisms (dCK and CTGF pathways) for gemcitabine resistance may be two novel targets for CYR61/CCN1 to protect pancreatic cancer cells from gemcitabine. Collectively, these studies reveal a novel paradigm in which CYR61/CCN1regulates both extrinsic and intrinsic gemcitabine resistance in PDAC cells by employing unique signaling pathways.

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Section: Maity Et Almentioning

confidence: 48%

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma

Maity

Ghosh

Gupta

et al. 2019

Molecular Cancer Therapeutics

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“…To demonstrate the utility of PhosID in a more relevant cellular context, we applied our optimized protocol to investigate Interferon-gamma (IFNγ) stimulation in two different cell lines. We adopted a classical AHA labeling workflow 41 to introduce 'click-able' azide functionalities into NSPs in HeLa and Jurkat cells, and then applied the PhosID strategy to identify NSPs induced by IFNγ in 4 or 24 h (Fig. 4a).…”

Section: Resultsmentioning

confidence: 99%

Fishing for newly synthesized proteins with phosphonate-handles

Kleinpenning

Steigenberger

et al. 2020

Nat Commun

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Bioorthogonal chemistry introduces affinity-labels into biomolecules with minimal disruption to the original system and is widely applicable in a range of contexts. In proteomics, immobilized metal affinity chromatography (IMAC) enables enrichment of phosphopeptides with extreme sensitivity and selectivity. Here, we adapt and combine these superb assets in a new enrichment strategy using phosphonate-handles, which we term PhosID. In this approach, click-able phosphonate-handles are introduced into proteins via 1,3-dipolar Huisgen-cycloaddition to azido-homo-alanine (AHA) and IMAC is then used to enrich exclusively for phosphonate-labeled peptides. In interferon-gamma (IFNγ) stimulated cells, PhosID enabled the identification of a large number of IFN responsive newly synthesized proteins (NSPs) whereby we monitored the differential synthesis of these proteins over time. Collectively, these data validate the excellent performance of PhosID with efficient analysis and quantification of hundreds of NSPs by single LC-MS/MS runs. We envision PhosID as an attractive and alternative tool for studying stimuli-sensitive proteome subsets.

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“…Noteworthy, the AKI also resulted in ambiguous epithelial/stromal identities. The heat map shows that the "Mixed Identity Cells" exhibit increased expression of stromal genes, particularly activated fibroblast markers (Ctgf, Col1a2, Cald1) (Shieh et al, 2019;Wu et al, 2018;Zhang et al, 2017b) ( Figure 1F) and genes related to the cell shape change and extracellular matrix remodeling (Sparc, Lgals3, Spp1, Myh9, S100a10) (Table S1), giving evidence for a more mesenchymal phenotype acquired by these cells in response to the injury. Epithelial-to-mesenchymal plasticity is a crucial contributor to the kidney injury and fibrosis (Humphreys, 2018;Lovisa et al, 2016).…”

Section: Cells In the Ischemia Reperfusion Induced Akimentioning

confidence: 99%

Single Cell Profiling of Acute Kidney Injury Reveals Novel Transcriptional Signatures, Mixed Identities and Epithelial-to-Stromal Crosstalk

Rudman-Melnick

Adam

Potter

et al. 2019

Preprint

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Acute kidney injury (AKI) is a rapid decline of renal function, with an incidence of up to 67% of intensive care unit patients. Current treatments are merely supportive, emphasizing the need for deeper understanding that could lead to improved therapies. We used single cell RNA sequencing, in situ hybridization and protein expression analyses to create comprehensive renal cell specific transcriptional profiles of multiple AKI stages. We revealed that AKI induces marked dedifferentiation, renal developmental gene activation and mixed identities in injured renal tubules. Moreover, we identified potential pathologic crosstalk between epithelial and stromal cells, and several novel genes involved in AKI. We also demonstrated the definitive effects of age on AKI outcome, and showed that renal developmental genes hold a potential as novel AKI markers. Moreover, our study provides the resource power which will aid in unraveling the molecular genetics of AKI.

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CTGF/VEGFA-activated Fibroblasts Promote Tumor Migration Through Micro-environmental Modulation

Cited by 13 publications

References 50 publications

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma

Fishing for newly synthesized proteins with phosphonate-handles

Single Cell Profiling of Acute Kidney Injury Reveals Novel Transcriptional Signatures, Mixed Identities and Epithelial-to-Stromal Crosstalk

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