DNA Methylation Mediates EMT Gene Expression in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Urbanova, Maria; Buociková, Verona; Trnkova, Lenka; Strapcova, Sabina; Kajabova, Viera Horvathova; Barreto, Emma; Novisedlakova, Maria; Tomáš, Miroslav; Dubovan, Peter; Earl, Julie; Bízik, Jozef; Švastová, Eliška; Ciernikova, Sona; Smolkova, Bozena

doi:10.3390/ijms23042117

Cited by 12 publications

(7 citation statements)

References 75 publications

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“…Similarly, the mRNA expression of CMYC, a marker of cell proliferation, was statistically reduced at 25 nM EC359 ( Figure 3 B). EC359 also reduced the expression of the EMT’s biomarkers Vimentin and Snail Family Transcriptional Repressor 1 (SNAIL-1) along with the expression of Chemokine receptor type 4 (CXCR4), a biomarker of PDAC aggressiveness that was also upregulated in the PADC tissues ( Figure 3 B) [ 43 ]. Vimentin is required for cell transition from the EMT state [ 44 ], and as shown in Figure 3 B, LIFR inhibition decreased both the genes as well as the assembly of vimentin filaments [ Figure 3 B] that are essential for cytoskeleton reorganization, cell spreading, and migration.…”

Section: Resultsmentioning

confidence: 99%

Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

Giorgio

Lupia

Marchianò

et al. 2022

Cells

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Pancreatic cancer is a leading cause of cancer mortality and is projected to become the second-most common cause of cancer mortality in the next decade. While gene-wide association studies and next generation sequencing analyses have identified molecular patterns and transcriptome profiles with prognostic relevance, therapeutic opportunities remain limited. Among the genes that are upregulated in pancreatic ductal adenocarcinomas (PDAC), the leukaemia inhibitory factor (LIF), a cytokine belonging to IL-6 family, has emerged as potential therapeutic candidate. LIF is aberrantly secreted by tumour cells and promotes tumour progression in pancreatic and other solid tumours through aberrant activation of the LIF receptor (LIFR) and downstream signalling that involves the JAK1/STAT3 pathway. Since there are no LIFR antagonists available for clinical use, we developed an in silico strategy to identify potential LIFR antagonists and drug repositioning with regard to LIFR antagonists. The results of these studies allowed the identification of mifepristone, a progesterone/glucocorticoid antagonist, clinically used in medical abortion, as a potent LIFR antagonist. Computational studies revealed that mifepristone binding partially overlapped the LIFR binding site. LIF and LIFR are expressed by human PDAC tissues and PDAC cell lines, including MIA-PaCa-2 and PANC-1 cells. Exposure of these cell lines to mifepristone reverses cell proliferation, migration and epithelial mesenchymal transition induced by LIF in a concentration-dependent manner. Mifepristone inhibits LIFR signalling and reverses STAT3 phosphorylation induced by LIF. Together, these data support the repositioning of mifepristone as a potential therapeutic agent in the treatment of PDAC.

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Section: Resultsmentioning

confidence: 99%

Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

Giorgio

Lupia

Marchianò

et al. 2022

Cells

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“…There have been several studies considering the effects of PDAC-cell-derived CM on other stromal components such as fibroblasts [ 11 ] and vice versa [ 20 , 21 ]. This work, however, is one of the first to consider the effects of PDAC-cell-derived CM on PC cells directly and specifically during gemcitabine and TRAIL treatment.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles Inhibit the Response of Pancreatic Ductal Adenocarcinoma Cells to Gemcitabine and TRAIL Treatment

Rimmer

Rashid

Kraev

et al. 2022

IJMS

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Pancreatic ductal adenocarcinoma remains an aggressive cancer with a low 5-year survival rate. Although gemcitabine has been a standard treatment for advanced pancreatic cancer, patients often develop resistance to this therapeutic. We have previously shown that treating pancreatic cancer cells in vitro with a combination of gemcitabine and the cytokine TRAIL significantly reduced both cell viability and survival. The data presented here demonstrate that this response to treatment is inhibited when cells are incubated with a conditioned medium derived from untreated cells. We show that this inhibition is specifically mediated by extracellular vesicles present in the conditioned medium, as seen by a significant decrease in apoptosis. Additionally, we further demonstrate that this effect can be reversed in the presence of GW4869, an inhibitor of exosome biogenesis and release. These results show that pancreatic cancer cell-derived extracellular vesicles can confer resistance to treatment with gemcitabine and TRAIL. The implications of these findings suggest that removal of EVs during treatment can improve the response of cells to gemcitabine and TRAIL treatment in vitro.

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“…Their availability increase research efforts in the field of cancer research. As such, these cell lines have been used to study different aspects of pancreatic cancer, including DNA methylation, RNA splicing, histone modification, EMT, TGFβ signaling, and anticancer drug testing 154–157 . Results from these studies have shown correlations between gene expression, activation of specific cellular pathways, and drug response.…”

Section: Late Diagnosismentioning

confidence: 99%

Advancements in Preclinical Models of Pancreatic Cancer

Salu,

Reindl

2024

Pancreas

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Pancreatic cancer remains one of the deadliest of all cancer types with a 5-year overall survival rate of just 12%. Preclinical models available for understanding the disease pathophysiology have evolved significantly in recent years. Traditionally, commercially available 2-dimensional cell lines were developed to investigate mechanisms underlying tumorigenesis, metastasis, and drug resistance. However, these cells grow as monolayer cultures that lack heterogeneity and do not effectively represent tumor biology. Developing patient-derived xenografts and genetically engineered mouse models led to increased cellular heterogeneity, molecular diversity, and tissues that histologically represent the original patient tumors. However, these models are relatively expensive and very timing consuming. More recently, the advancement of fast and inexpensive in vitro models that better mimic disease conditions in vivo are on the rise. Three-dimensional cultures like organoids and spheroids have gained popularity and are considered to recapitulate complex disease characteristics. In addition, computational genomics, transcriptomics, and metabolomic models are being developed to simulate pancreatic cancer progression and predict better treatment strategies. Herein, we review the challenges associated with pancreatic cancer research and available analytical models. We suggest that an integrated approach toward using these models may allow for developing new strategies for pancreatic cancer precision medicine.

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DNA Methylation Mediates EMT Gene Expression in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Cited by 12 publications

References 75 publications

Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

Extracellular Vesicles Inhibit the Response of Pancreatic Ductal Adenocarcinoma Cells to Gemcitabine and TRAIL Treatment

Advancements in Preclinical Models of Pancreatic Cancer

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