Homo sapiens
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PROVIDER: PRJNA252428 | ENA |
REPOSITORIES: ENA
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Project description:In pancreatic cancer the survival rate is low, as the available treatment options usually only extend survival and seldom produce a cure. Drug resistance and disease reoccurrence is the typical reason for death after cancer diagnosis. 5-Fluorouracil (5-FU) is the main chemostatic used in first line therapy. However the majority of the tumors become resistant to treatment. To investigate acquired 5-FU resistance in pancreatic adenocarcinoma, we established chemoresistant monoclonal cell lines from the Panc03.27 cell line by long-term exposure to 5-FU. In addition to increased expression of markers associated with multidrug resistance, the 5-FU resistant clones showed alterations typical of the process of epithelial-to-mesenchymal transition (EMT), including upregulation of mesenchymal markers and increased invasiveness. Microarray analysis revealed the L1CAM pathway as one of the most upregulated pathways in the chemoresistant clones, which was confirmed on RNA and protein levels. Expression of the adhesion molecule L1CAM is associated with a chemoresistant and migratory phenotype of pancreatic cancer. Using esiRNA targeting L1CAM, or by blocking the extracellular part of L1CAM with monoclonal antibodies, we discovered that the increased invasiveness observed in the chemoresistant cells depends on L1CAM. Using esiRNA targeting β-catenin and/or Slug, we discovered that L1CAM expression depends on Slug rather than β-catenin in the 5-FU resistant cells. We demonstrate a functional link between Slug and the expression level of L1CAM in pancreatic cancer cells having undergone EMT following long-term exposure to 5-FU. Our findings provide further insight into the molecular mechanisms leading to a chemoresistant and migratory phenotype in pancreatic cancer cells and indicate the importance of Slug-induced L1CAM in refractory pancreatic cancer. Examination of expression of 5-Fluorouracil (5-FU) Panc03.27 cell line resistant clone versus expression of 5-FU sensitive clones (NT) in 4 replicates per cell lines
2015-08-11 | E-GEOD-58386 | biostudies-arrayexpress
Project description:In pancreatic cancer the survival rate is low, as the available treatment options usually only extend survival and seldom produce a cure. Drug resistance and disease reoccurrence is the typical reason for death after cancer diagnosis. 5-Fluorouracil (5-FU) is the main chemostatic used in first line therapy. However the majority of the tumors become resistant to treatment. To investigate acquired 5-FU resistance in pancreatic adenocarcinoma, we established chemoresistant monoclonal cell lines from the Panc03.27 cell line by long-term exposure to 5-FU. In addition to increased expression of markers associated with multidrug resistance, the 5-FU resistant clones showed alterations typical of the process of epithelial-to-mesenchymal transition (EMT), including upregulation of mesenchymal markers and increased invasiveness. Microarray analysis revealed the L1CAM pathway as one of the most upregulated pathways in the chemoresistant clones, which was confirmed on RNA and protein levels. Expression of the adhesion molecule L1CAM is associated with a chemoresistant and migratory phenotype of pancreatic cancer. Using esiRNA targeting L1CAM, or by blocking the extracellular part of L1CAM with monoclonal antibodies, we discovered that the increased invasiveness observed in the chemoresistant cells depends on L1CAM. Using esiRNA targeting β-catenin and/or Slug, we discovered that L1CAM expression depends on Slug rather than β-catenin in the 5-FU resistant cells. We demonstrate a functional link between Slug and the expression level of L1CAM in pancreatic cancer cells having undergone EMT following long-term exposure to 5-FU. Our findings provide further insight into the molecular mechanisms leading to a chemoresistant and migratory phenotype in pancreatic cancer cells and indicate the importance of Slug-induced L1CAM in refractory pancreatic cancer.
2015-08-11 | GSE58386 | GEO
Project description:Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of glutamine can lead to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression. Here, we show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the upregulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation-induced EMT, cell motility and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression.
2020-05-20 | GSE150874 | GEO
Project description:Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of glutamine can lead to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression. Here, we show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the upregulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation-induced EMT, cell motility and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression.
2020-05-20 | GSE150873 | GEO
Project description:Drug-tolerant persister (DTP) cells remain following chemotherapy and can cause cancer relapse. However, it is unclear when acquired resistance to chemotherapy emerges. Here, we compared the gene expression profiles of gastric cancer patient-derived cells (GC PDCs) and their respective xenograft tumors with different sensitivities to 5-fluorouracil (5-FU) by using immunodeficient female BALB/c-nu mice. RNA sequencing analysis of 5-FU-treated PDCs demonstrated that DNA replication/cell cycle-related genes were transiently induced in the earlier phase of DTP cell emergence, while extracellular matrix (ECM)-related genes were sustainably upregulated during long-term cell survival in 5-FU-resistant residual tumors. NicheNet analysis, which uncovers cell-cell signal interactions, indicated the transforming growth factor-β (TGF-β) pathway as the upstream regulator in response to 5-FU treatment. This induced ECM-related gene expression in the 5-FU-resistant tumor model. In the 5-FU-resistant residual tumors, there was a marked upregulation of cancer cell-derived TGF-β1 expression and increased phosphorylation of SMAD3, a downstream regulator of the TGF-β receptor. By contrast, these responses were not observed in a 5-FU-sensitive tumor model. We further found that TGF-β-related upregulation of ECM genes was preferentially observed in non-responders to chemotherapy with 5-FU and/or oxaliplatin among 22 patient-derived xenograft tumors. These observations suggest that chemotherapy-induced activation of the TGF-β1/SMAD3/ECM-related gene axis is a potential biomarker for the emergence of drug resistance in GCs.
2024-05-30 | GSE264144 | GEO
Project description:Resistance to MEK1/2 inhibition through Slug upregulation in pancreatic cancer
| PRJNA719991 | ENA
Project description:The mechanisms involved in promoting metastasis of pancreatic ductal adenocarcinoma have yet to be elucidated. Here, we show that AnnexinA2 regulates the secretion of Semaphorin3D from pancreatic tumor cells allowing it to bind to its receptor PlexinD1 on the surface of the tumor cell, which induces invasion and metastasis. Knockdown of AnnexinA2 or Semaphorin3D decreases the metastatic potential of pancreatic tumor cells, while over expression of AnnexinA2 or Semaphorin3D is sufficient to rescue the invasion capacity of these cells. Clinically, we found that Semaphorin3D expression correlates with poor survival and increased metastatic potential in human PDA patients. This study identified a novel axon guidance pathway downstream of AnnexinA2 that can be targeted in the treatment of metastatic pancreatic cancer. Two primary pancreatic tumor cell lines were analyzed. The first primary line was derived from a KrasG12D/p53172H/Pdx-1Cre mouse, which served as the reference sample. The second primary line was derived from a KrasG12D/p53R172H/Pdx-1Cre/AnxA2-/- mouse.
2015-09-03 | E-GEOD-62285 | biostudies-arrayexpress
Project description:Chronic inflammation facilitates tumor progression. We discovered that a subset of non-small cell lung cancer cells underwent a gradually progressing epithelial-to-mesenchymal (EMT) phenotype following a 21-day exposure to IL-1β, an abundant proinflammatory cytokine in the at-risk for lung cancer pulmonary and the lung tumor microenvironments. Pathway analysis of the gene expression profile and in vitro functional studies revealed that the EMT and EMT-associated phenotypes, including enhanced cell invasion, PD-L1 upregulation, and chemoresistance, were sustained in the absence of continuous IL-1β exposure. We referred to this phenomenon as EMT memory. Utilizing a doxycycline-controlled SLUG expression system, we found that high expression of the transcription factor SLUG was indispensable for the establishment of EMT memory. High SLUG expression in tumors of lung cancer patients was associated with poor survival. Chemical or genetic inhibition of SLUG upregulation prevented EMT following the acute IL-1β exposure but did not reverse EMT memory. Chromatin immunoprecipitation and methylation-specific PCR further revealed a SLUG-mediated temporal regulation of epigenetic modifications, including accumulation of H3K27, H3K9, and DNA methylation, in the CDH1 (E-cadherin) promoter following the chronic IL-1β exposure. Chemical inhibition of DNA methylation not only restored E-cadherin expression in EMT memory, but also primed cells for chemotherapy-induced apoptosis.
2019-12-27 | GSE142620 | GEO
Project description:The mechanisms involved in promoting metastasis of pancreatic ductal adenocarcinoma have yet to be elucidated. Here, we show that AnnexinA2 regulates the secretion of Semaphorin3D from pancreatic tumor cells allowing it to bind to its receptor PlexinD1 on the surface of the tumor cell, which induces invasion and metastasis. Knockdown of AnnexinA2 or Semaphorin3D decreases the metastatic potential of pancreatic tumor cells, while over expression of AnnexinA2 or Semaphorin3D is sufficient to rescue the invasion capacity of these cells. Clinically, we found that Semaphorin3D expression correlates with poor survival and increased metastatic potential in human PDA patients. This study identified a novel axon guidance pathway downstream of AnnexinA2 that can be targeted in the treatment of metastatic pancreatic cancer.
2015-09-03 | GSE62285 | GEO
Project description:Background: The well-characterized function of the transcriptional repressor, Slug, is to promote EMT and tumor invasion/metastasis by down-regulating E-cadherin expression. In this study, we investigated the significance of Slug during the S phase. Method: Slug mRNA expression was isolated from thymidine-arrested CL1-5/AS2neo (control) and CL1-5/AS2neo-Slug-WT stable cells. The Agilent oligonucleotide microarray analysis was performed to identify Slug downstream genes. Results: Overexpression of Slug inhibited lung [3H]-thymidine incorporation and delayed S phase progression. By using Agilent microarray we have identified panel of genes altered by Slug overexpression. Slug can down-regulate target genes about cell cycle networks for DNA replication, DNA replication checkpoint and genomic stability, such as TOP1, ORC4, RFC3, and Rad17. Conclusions: the multifaceted role of Slug in cancer progression by controlling the epithelial-mesenchymal transition and genome stability. Two-condition experiment, Vector vs. Slug overexpression cells. The cDNAs encoding full-length human Slug were amplified and subcloned into lentiviral pLKO_AS2.neo which generated full-length Slug. Vector control or Slug lentivirus were transduced into CL1-5 cells and Gentamycin was used to select stable cells.
2012-02-09 | E-GEOD-35617 | biostudies-arrayexpress