Subtypes in human pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses
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ABSTRACT:
PROVIDER: PRJNA752619 | ENA |
REPOSITORIES: ENA
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Project description:BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses. METHODS: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared. RESULTS: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were significantly more sensitive to simvastatin than poorly differentiated PDOs. CONCLUSIONS: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.
2021-08-07 | GSE181593 | GEO
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses.MethodsThe molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared.ResultsThe expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were more sensitive to simvastatin than poorly differentiated PDOs.ConclusionsOur findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.
| S-EPMC8908673 | biostudies-literature
Project description:To evaluate the prognostic relevance of molecular subtypes and key transcription factors in pancreatic ductal adenocarcinoma (PDAC), we performed gene expression analysis of whole-tumor tissue obtained from 118 surgically resected PDAC and 13 control samples.
2016-08-17 | GSE62165 | GEO
Project description:We generated novel patient derived xenograft (PDX) and cell line -derived xenograft models for pancreatic ductal adenocarcinoma (PDAC) which reflect different molecular subtypes. Pancreatic ductal adenocarcinoma is currently the tumor with the fourth highest mortality rate. Recently, subtypes of PDAC have been reported by Collisson et al (Nat. Med. 17(4) 2011. DOI: 10.1038/nm.2344). However current fetal calf serum (FCS) cultured cell lines do not accurately model these subtypes. We thus generated novel serum-free cell lines derived from primary patient xenografts. We here analyse the gene-expression profiles of the xenografts and the derived cell lines. We show that indeed three different subtypes can be separated in our models based on gene-expression data. Further, we identify upregulation of a drug-detoxification pathway specifically in xenografts and cell lines of one of the subtypes. These models and data will help to better understand inter-patient heterogeneity in PDAC and identify novel drug targets and diagnostic markers.
2016-01-12 | E-MTAB-4029 | biostudies-arrayexpress
Project description:Myeloproliferative neoplasms show different signature in megakaryocyte-erythroid progenitors among different subtypes
| PRJNA707039 | ENA
Project description:Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis and current treatments are only modestly effective. We present evidence that this variation is caused in part by recurrent, pervasive molecular differences between tumors. mRNA expression profiles measured using microdissected PDA clinical samples reveal three dominant subtypes of disease; epithelial, mesenchymal and acinar-like. The classical and quasi-mesenchymal subtypes are observed in human and mouse PDA cell lines. Importantly, responses to cytotoxics and KRAS depletion in human PDA cell lines differ substantially between subtypes, and in opposing directions. Integrated genomics implicate and functional studies support overexpression of the trancription factor GATA6 as a driver of the epithelial subtype. These results provide a molecular framework for evaluating the prospects of personalized treatment in PDA.
2011-04-01 | GSE17891 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here, we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, which includes primary, metastatic, and normal samples. By digitally separating tumor, stroma, and normal gene expression, we have identified and validated two tumor-specific subtypes including a “basal-like†subtype which has worse outcome, and is molecularly similar to basal tumors in bladder and breast cancer. Furthermore, we define 'normal' and 'activated' stromal subtypes which are independently prognostic. Our results provide new insight into the molecular composition of PDAC which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies is critical. Analysis of the landscape of gene expression in pancreatic adenocarcinoma. Data include 145 primary and 61 metastatic PDAC tumors, 17 cell lines, 46 pancreas and 88 distant site adjacent normal samples. Arrays represent distinct samples. The SPOT column in the raw data file (linked to each sample record) contains Agilent feature extraction numbers (included in the 'GPL4133-20424.txt' linked to the platform records).
2015-09-07 | E-GEOD-71729 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis and current treatments are only modestly effective. We present evidence that this variation is caused in part by recurrent, pervasive molecular differences between tumors. mRNA expression profiles measured using microdissected PDA clinical samples reveal three dominant subtypes of disease; epithelial, mesenchymal and acinar-like. The classical and quasi-mesenchymal subtypes are observed in human and mouse PDA cell lines. Importantly, responses to cytotoxics and KRAS depletion in human PDA cell lines differ substantially between subtypes, and in opposing directions. Integrated genomics implicate and functional studies support overexpression of the trancription factor GATA6 as a driver of the epithelial subtype. These results provide a molecular framework for evaluating the prospects of personalized treatment in PDA. RNA was extracted from archival patient FFPE PDA samples and hybridized on Affymetrix U133 plus 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA. RNA was extracted from human PDA cell line samples and hybridized on Affymetrix U133 plus 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA. RNA was extracted from mouse PDA cell lines and hybridized on Affymetrix Mouse 430a 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA.
2011-04-01 | E-GEOD-17891 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here, we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, which includes primary, metastatic, and normal samples. By digitally separating tumor, stroma, and normal gene expression, we have identified and validated two tumor-specific subtypes including a “basal-like†subtype which has worse outcome, and is molecularly similar to basal tumors in bladder and breast cancer. Furthermore, we define 'normal' and 'activated' stromal subtypes which are independently prognostic. Our results provide new insight into the molecular composition of PDAC which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies is critical.
2015-09-07 | GSE71729 | GEO