Combating pancreatic cancer with ovarian cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE212173 | GEO | 2022/08/30
REPOSITORIES: GEO
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a nearly uniformly lethal malignancy, with most patients facing an adverse clinical outcome. Given the pivotal role of aberrant Notch signaling in the initiation and progression of PDAC, we investigated the effect of MRK-003, a potent and selective γ-secretase inhibitor, in preclinical PDAC models. We used a panel of human PDAC cell lines, as well as patient-derived PDAC xenografts, to determine whether pharmacological targeting of the Notch pathway could inhibit pancreatic tumor growth and potentiate gemcitabine sensitivity. In vitro, MRK-003 treatment downregulated the canonical Notch target gene Hes-1, significantly inhibited anchorage independent growth, and reduced the subset of CD44+CD24+ and aldehyde dehydrogenase (ALDH)+ cells that have been attributed with tumor initiating capacity. Ex vivo pretreatment of PDAC cells with MRK-003 in culture significantly inhibited the subsequent engraftment in immunocompromised mice. In vivo, MRK-003 monotherapy significantly blocked tumor growth in 5 of 9 (56%) patient-derived PDAC xenografts. Moreover, a combination of MRK-003 and gemcitabine showed enhanced antitumor effects compared to gemcitabine alone in 4 of 9 (44%) PDAC xenografts. Baseline gene expression analysis of the treated xenografts indicated that upregulation of nuclear factor kappa B (NFκB) pathway components was associated with the sensitivity to single MRK-003, while upregulation in B-cell receptor (BCR) signaling and nuclear factor erythroid-derived 2-like 2 (NRF2) pathway correlated with response to the combination of MRK-003 with gemcitabine. The preclinical findings presented here provide further rationale for small molecule inhibition of Notch signaling as a therapeutic strategy in PDAC. Pancreatic ductal adenocarcinoma xenografts were grown in Athymic Nude-Foxn1nu mice. RNA was extracted and profiled in Affymetrix platform to identify genes correlating with sensitivity to MRK-003
2012-05-02 | E-GEOD-37645 | biostudies-arrayexpress
Project description:Gemcitabine (GEM) is a key drug for treating PDAC, and it is commonly used for adjuvant chemotherapy. Although the majority of PDAC is sensitive to GEM at first, GEM cannot control PDAC for very long, suggesting that PDAC develops resistance to GEM after prolonged exposure. No reliable predictors of susceptibility to gemcitabine chemotherapy exist in pancreatic ductal adenocarcinoma. This study assesses gemcitabine resistant PDAC for its specific mRNA expression pattern. Gemcitabine resistant variants of Panc1, a human pancreatic adenocarcinoma cell line, were established. mRNA screening was investigated by microarray.
2016-04-26 | GSE80617 | GEO
Project description:Gemcitabine (GEM) is a key drug for treating PDAC, and it is commonly used for adjuvant chemotherapy. Although the majority of PDAC is sensitive to GEM at first, GEM cannot control PDAC for very long, suggesting that PDAC develops resistance to GEM after prolonged exposure. No reliable predictors of susceptibility to gemcitabine chemotherapy exist in pancreatic ductal adenocarcinoma. MicroRNAs (miR) are epigenetic gene regulators with tumorsuppressive or oncogenic roles in various carcinomas. This study assesses gemcitabine resistant PDAC for its specific miR expression pattern. Gemcitabine resistant variants of Panc1, a human pancreatic adenocarcinoma cell line, were established. MicroRNA screening was investigated by microarray.
2016-04-26 | GSE80616 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer associated fibroblasts (CAFs). CAFs promote tumor growth, metastasis and treatment resistance. We aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAFs) were generated by continuous incubation in 100nM gemcitabine. Gene expression differences between treatment naïve CAFs (N-CAFs) and R-CAFs were compared by array analysis. Immortalized human pancreatic CAFs were grown for 30 days in either control media or media containing 100nM gemcitabine. RNA was then isolated and hybidized on U133 Plus 2.0 Affymetrix arrays.
2016-03-09 | E-GEOD-78982 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a nearly uniformly lethal malignancy, with most patients facing an adverse clinical outcome. Given the pivotal role of aberrant Notch signaling in the initiation and progression of PDAC, we investigated the effect of MRK-003, a potent and selective γ-secretase inhibitor, in preclinical PDAC models. We used a panel of human PDAC cell lines, as well as patient-derived PDAC xenografts, to determine whether pharmacological targeting of the Notch pathway could inhibit pancreatic tumor growth and potentiate gemcitabine sensitivity. In vitro, MRK-003 treatment downregulated the canonical Notch target gene Hes-1, significantly inhibited anchorage independent growth, and reduced the subset of CD44+CD24+ and aldehyde dehydrogenase (ALDH)+ cells that have been attributed with tumor initiating capacity. Ex vivo pretreatment of PDAC cells with MRK-003 in culture significantly inhibited the subsequent engraftment in immunocompromised mice. In vivo, MRK-003 monotherapy significantly blocked tumor growth in 5 of 9 (56%) patient-derived PDAC xenografts. Moreover, a combination of MRK-003 and gemcitabine showed enhanced antitumor effects compared to gemcitabine alone in 4 of 9 (44%) PDAC xenografts. Baseline gene expression analysis of the treated xenografts indicated that upregulation of nuclear factor kappa B (NFκB) pathway components was associated with the sensitivity to single MRK-003, while upregulation in B-cell receptor (BCR) signaling and nuclear factor erythroid-derived 2-like 2 (NRF2) pathway correlated with response to the combination of MRK-003 with gemcitabine. The preclinical findings presented here provide further rationale for small molecule inhibition of Notch signaling as a therapeutic strategy in PDAC.
2012-05-03 | GSE37645 | GEO
Project description:Cancer associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic adenocarcinomas (PDACs). Current efforts to eradicate these tumors focus predominantly on targeting the proliferation of rapidly growing cancer epithelial cells. We know that this is largely ineffective with resistance arising in most tumors following exposure to chemotherapy. Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of chemotherapy on CAFs and how they may contribute to drug resistance in neighboring cancer cells is not well characterized. Here we show that CAFs exposed to chemotherapy play an active role in regulating the survival and proliferation of cancer cells. We found that CAFs are intrinsically resistant to gemcitabine, the chemotherapeutic standard of care for PDAC. Further, CAFs exposed to gemcitabine significantly increase the release of extracellular vesicles called exosomes. These exosomes increased chemoresistance-inducing factor, Snail, in recipient epithelial cells and promote proliferation and drug resistance. Finally, treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly reduces survival in co-cultured epithelial cells, signifying an important role of CAF exosomes in chemotherapeutic drug resistance. Collectively, these findings show the potential for exosome inhibitors as treatment options alongside chemotherapy for overcoming PDAC chemoresistance.
2016-11-01 | GSE85048 | GEO
Project description:BACKGROUND: Therapy resistance remains one of the major challenges to improve the prognosis of patients with pancreatic cancer. Chemoresistant cells, which potentially also display cancer stem cell (CSC) characteristics, can be isolated using the side population (SP) technique. Our aim was to search for a SP in human pancreatic ductal adenocarcinoma (PDAC) and to examine its chemoresistance and CSC phenotype. RESULTS: A SP was identified in all PDAC samples, expanded and analyzed as first-generation xenografts. This SP was more resistant to gemcitabine than the other tumour cells as analyzed in vivo. Whole-genome expression profiling of the SP revealed upregulation of genes related to therapy resistance, apoptotic regulation and epithelial-mesenchymal transition. In addition, the SP displayed higher tumourigenic (CSC) activity than the other main tumour cell population (MP) as analyzed in vitro by sphere-forming capacity. CONCLUSION: We identified a SP in human PDAC and uncovered a chemoresistant and CSC-associated phenotype. This SP may represent a new therapeutic target in pancreatic cancer. Micro-array analysis was performed on SP and MP samples of 5 xenografts, grown from 5 different human PDAC samples.
2016-01-04 | E-GEOD-36563 | biostudies-arrayexpress
Project description:Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC) but patients often show poor or complete lack of response to this agent. Molecular markers downstream of Gemcitabine treatment in pre-clinical models may provide an insight into resistance mechanisms. We identified potential secretory biomarkers of Gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC using cytokine arrays. We validated the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) in primary pancreatic tumours and metastasis using both in vitro techniques and animal models. We identified potential pathways affected downstream of TIMP-1 using the Illumina Human H12 array. Our findings were validated in both primary and metastatic models of pancreatic cancer. Gemcitabine increases inflammatory cytokines including TIMP-1 in the KPC mouse model. TIMP-1 is upregulated in patients with pancreatic intraepithelial neoplasias grade 3 and PDAC lesions relative to matched normal pancreatic tissue. Additionally, we demonstrate that TIMP-1 plays a role in tumour proliferation and angiogenesis, while inhibition resensitises to gemcitabine and radiotherapy. Strikingly, serum TIMP-1 levels support the formation of liver metastasis through the recruitment of immunosuppressive cell populations, such as CD11b+Gr1+ myeloid cells and CD4+CD25+FOXP3+ Tregs to the hepatic microenvironment. Gemcitabine treatment results in upregulation of the pro-tumourigenic/pro-metastatic cytokine TIMP-1, which partially explains the therapeutic resistance and poor responses to this therapy in PDAC. Our study provides a rationale for the development and testing of TIMP-1 specific inhibitors in addition to chemo/radiotherapy.
2017-08-08 | GSE94891 | GEO
Project description:Pancreatic cancer (Pancreatic Ductal Adenocarcinoma; PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, and therefore, chemotherapy remains the best available systematic treatment. The discovery of safe and available adjuncts that can improve chemotherapeutic efficacy could potentially improve survival outcomes. We show that a hyperglycemic state enhances the efficacy of conventional single- and multi-agent chemotherapies against PDAC. Molecular analyses of tumors exposed to relatively high glucose levels revealed that GCLC (catalytic subunit of glutamate-cysteine ligase), a key regulator of a metabolic pathway, glutathione biosynthesis, is diminished and underlies chemo-sensitization. Inhibition to GCLC phenocopied the effect of an induced hyperglycemic state in mouse models of PDAC, while rescuing the pathway abrogated the anti-tumor effects observed with chemotherapy treatment under high glucose conditions.
2022-10-18 | MTBLS6000 | MetaboLights
Project description:Pancreatic Ductal Adenocarcinoma (PDAC) is associated with extremely poor prognosis due to late diagnosis and therapeutic resistance. Here we show that PDAC cells undergo progressive reprogramming of the global epigenetic landscape during the process of acquiring chemoresistance. Through an epigenetic inhibitor screen, we identified Protein Arginine methyltransferase 1 (PRMT1) as a central driver of chemoresistance in PDAC. Genetic or pharmacological inhibition of PRMT1 impaired adaptive epigenetic reprogramming, sensitized PDAC cells to Gemcitabine and other commonly used chemo drugs, and delayed the development of acquired resistance both in vitro and in vivo. Mechanistically, we find that PRMT1, through its enzymatic activity, limits the accumulation of small bZIP transcription factor MAFF in the nucleus, and the assembly of chromatin-bound MAFF/BACH1 hetero-oligomeric complexes following Gemcitabine treatment. Genetic silencing of MAFF heightened the resistance of PDAC cells to Gemcitabine, and to combination of Gemcitabine and PRMT1 inhibitors. Cut&Tag chromatin profiling of H3K27Ac, MAFF and BACH1 suggests a pivotal role for MAFF/BACH1 in orchestrating global epigenetic reprogramming during the course of acquiring Gemcitabine resistance. Supporting the clinical relevance of our findings, predicted PRMT1 and MAFF/BACH1 genes signatures based on our Cut&Tag analysis were able to distinguish Gemcitabine-resistant from Gemcitabine-sensitive PDAC patient-derived xenografts according to expression changes induced by Gemcitabine. Together, our study reveals a novel epigenetic regulatory axis involving PRMT1 and MAFF/BACH1 that modulates Gemcitabine response, which could be potentially exploited for improving therapeutic response in advanced PDAC.
2024-04-29 | GSE227129 | GEO