Reciprocal Regulation of Pancreatic Ductal Adenocarcinoma Growth and Molecular Subtype by HNF4a and SIX1/4
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ABSTRACT:
PROVIDER: PRJNA575905 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-01-14 | GSE138463 | GEO
Project description:ObjectivePancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: classical and basal-like. The classical subtype is characterised by a more favourable prognosis and better response to chemotherapy than the basal-like subtype. The classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor hepatocyte nuclear factor 4 α (HNF4α). The objective of this study is to evaluate the role of HNF4α, SIX4 and SIX1 in regulating the growth and molecular subtype of PDAC.DesignWe manipulate the expression of HNF4α, SIX4 and SIX1 in multiple in vitro and in vivo PDAC models. We determine the consequences of manipulating these genes on PDAC growth, differentiation and molecular subtype using functional assays, gene expression analysis and cross-species comparisons with human datasets.ResultsWe show that HNF4α restrains tumour growth and drives tumour cells toward an epithelial identity. Gene expression analysis of murine models and human tumours shows that HNF4α activates expression of genes associated with the classical subtype. HNF4α also directly represses SIX4 and SIX1, two mesodermal/neuronal lineage specifiers expressed in the basal-like subtype. Finally, SIX4 and SIX1 drive proliferation and regulate differentiation in HNF4α-negative PDAC.ConclusionOur data show that HNF4α regulates the growth and molecular subtype of PDAC by multiple mechanisms, including activation of the classical gene expression programme and repression of SIX4 and SIX1, which may represent novel dependencies of the basal-like subtype.
| S-EPMC7945295 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma is aggressive disease with a dismal five-year survival of 5%. Gene expression profiling has been instrumental for subtype classification in cancer, highlighting fundamental differences in tumors at the molecular level. Over the last years, multiple genomics studies have led to the classification of PDAC into two major subtypes: classical and basal-type. The classical subtype expresses higher levels of endodermal lineage specifiers, including HNF4A, GATA6, FOXA2, FOXA3 than the basal-type. The basal-type confers a worse prognosis, raising the possibility that loss of these lineage specifiers might enhance the malignant potential of PDAC. We found that the lineage specifier HNF4a plays a key role in maintaining a transcriptional network that characterizes the classical subtype, restraining growth in different PDAC models. Additionally, we demonstrated that HNF4a controls PDAC cell identity and proliferation, and represses the expression of SIX family members, two mesodermal lineage specifiers highly expressed in basal-type.
2021-01-14 | GSE138452 | GEO
Project description:Pancreatic ductal adenocarcinoma is an aggressive disease with a dismal five-year survival of 5%. Gene expression profiling has been instrumental for subtype classification in cancer, highlighting fundamental differences in tumors at the molecular level. Over the last years, multiple genomics studies have led to the classification of PDAC into two major subtypes: classical and basal-type. The classical subtype expresses higher levels of endodermal lineage specifiers, including HNF4A, GATA6, FOXA2, FOXA3 than the basal-type. The basal-type confers a worse prognosis, raising the possibility that loss of these lineage specifiers might enhance the malignant potential of PDAC. We found that the lineage specifier HNF4a plays a key role in maintaining a transcriptional network that characterizes the classical subtype, restraining growth in different PDAC models. Additionally, we demonstrated that HNF4a controls PDAC cell identity and proliferation, and represses the expression of SIX family members, two mesodermal lineage specifiers highly expressed in basal-type.
2021-01-14 | GSE138144 | GEO
Project description:Pancreatic ductal adenocarcinoma is aggressive disease with a dismal five-year survival of 5%. Gene expression profiling has been instrumental for subtype classification in cancer, highlighting fundamental differences in tumors at the molecular level. Over the last years, multiple genomics studies have led to the classification of PDAC into two major subtypes: classical and basal-type. The classical subtype expresses higher levels of endodermal lineage specifiers, including HNF4A, GATA6, FOXA2, FOXA3 than the basal-type. The basal-type confers a worse prognosis, raising the possibility that loss of these lineage specifiers might enhance the malignant potential of PDAC. We found that the lineage specifier HNF4a plays a key role in maintaining a transcriptional network that characterizes the classical subtype, restraining growth in different PDAC models. Additionally, we demonstrated that HNF4a controls PDAC cell identity and proliferation, and represses the expression of SIX family members, two mesodermal lineage specifiers highly expressed in basal-type.
2021-01-14 | GSE138451 | GEO
Project description:Pancreatic ductal adenocarcinoma is aggressive disease with a dismal five-year survival of 5%. Gene expression profiling has been instrumental for subtype classification in cancer, highlighting fundamental differences in tumors at the molecular level. Over the last years, multiple genomics studies have led to the classification of PDAC into two major subtypes: classical and basal-type. The classical subtype expresses higher levels of endodermal lineage specifiers, including HNF4A, GATA6, FOXA2, FOXA3 than the basal-type. The basal-type confers a worse prognosis, raising the possibility that loss of these lineage specifiers might enhance the malignant potential of PDAC. We found that the lineage specifier HNF4a plays a key role in maintaining a transcriptional network that characterizes the classical subtype, restraining growth in different PDAC models. Additionally, we demonstrated that HNF4a controls PDAC cell identity and proliferation, and represses the expression of SIX family members, two mesodermal lineage specifiers highly expressed in basal-type.
2021-01-14 | GSE144750 | GEO
Project description:Pancreatic ductal adenocarcinoma is an aggressive disease with a dismal five-year survival of 5%. Gene expression profiling has been instrumental for subtype classification in cancer, highlighting fundamental differences in tumors at the molecular level. Over the last years, multiple genomics studies have led to the classification of PDAC into two major subtypes: classical and basal-type. The classical subtype expresses higher levels of endodermal lineage specifiers, including HNF4A, GATA6, FOXA2, FOXA3 than the basal-type. The basal-type confers a worse prognosis, raising the possibility that loss of these lineage specifiers might enhance the malignant potential of PDAC. We found that the lineage specifier HNF4a plays a key role in maintaining a transcriptional network that characterizes the classical subtype, restraining growth in different PDAC models. Additionally, we demonstrated that HNF4a controls PDAC cell identity and proliferation, and represses the expression of SIX family members, two mesodermal lineage specifiers highly expressed in basal-type.
2021-01-14 | GSE138143 | GEO
Project description:Pancreatic ductal adenocarcinoma is an aggressive disease with a dismal five-year survival of 5%. Gene expression profiling has been instrumental for subtype classification in cancer, highlighting fundamental differences in tumors at the molecular level. Over the last years, multiple genomics studies have led to the classification of PDAC into two major subtypes: classical and basal-type. The classical subtype expresses higher levels of endodermal lineage specifiers, including HNF4A, GATA6, FOXA2, FOXA3 than the basal-type. The basal-type confers a worse prognosis, raising the possibility that loss of these lineage specifiers might enhance the malignant potential of PDAC. We found that the lineage specifier HNF4a plays a key role in maintaining a transcriptional network that characterizes the classical subtype, restraining growth in different PDAC models. Additionally, we demonstrated that HNF4a controls PDAC cell identity and proliferation, and represses the expression of SIX family members, two mesodermal lineage specifiers highly expressed in basal-type.
2021-01-14 | GSE138142 | GEO
Project description:Investigating genomic binding of SIX1 in A673 cells transduced with shSCR or one of two shSIX1 shRNAs to deplete SIX1.
2023-05-22 | GSE215350 | GEO