Identification of ALDH1A3 as a viable therapeutic target in breast cancer metastasis-initiating cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA575571 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10223738_1.fastq.gz | Fastqsanger.gz | |||
| SRR10223738_2.fastq.gz | Fastqsanger.gz | |||
| SRR10223739_1.fastq.gz | Fastqsanger.gz | |||
| SRR10223739_2.fastq.gz | Fastqsanger.gz | |||
| SRR10223740_1.fastq.gz | Fastqsanger.gz |
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Project description:The development of efficacious therapies targeting metastatic spread of breast cancer to the brain represents an unmet clinical need. Accordingly, an improved understanding of the molecular underpinnings of central nervous system spread and progression of breast cancer brain metastases (BCBM) is required. In this study, the clinical burden of disease in BCBM was investigated, as well as the role of aldehyde dehydrogenase 1A3 (ALDH1A3) in the metastatic cascade leading to BCBM development. Initial analysis of clinical survival trends for breast cancer and BCBM determined improvement of breast cancer survival rates, however this has failed to positively impact the prognostic milestones of triple-negative breast cancer (TNBC) brain metastases (BM). ALDH1A3 and a representative epithelial-mesenchymal transition (EMT) gene signature (mesenchymal markers CD44, Vimentin) were compared in tumors derived from BM, lung metastases (LM) or bone metastases (BoM) of patients as well as mice post-injection of TNBC cells. Selective elevation of the EMT signature and ALDH1A3 were observed in BM, unlike LM and BoM, especially in the tumor edge. Furthermore, ALDH1A3 was determined to play a role in BCBM establishment via regulation of circulating tumor cell (CTC) adhesion and migration phases in the BCBM cascade. Validation through genetic and pharmacologic inhibition of ALDH1A3 via lentiviral shRNA knockdown and a novel small molecule inhibitor demonstrated selective inhibition of BCBM formation with prolonged survival of tumor-bearing mice. Given the survival benefits via targeting ALDH1A3, it may prove an effective therapeutic strategy for BCBM prevention and/or treatment.
2020-01-01 | GSE138361 | GEO
Project description:The development of efficacious therapies targeting metastatic spread of breast cancer to the brain represents an unmet clinical need. Accordingly, an improved understanding of the molecular underpinnings of central nervous system spread and progression of breast cancer brain metastases (BCBM) is required. In this study, the clinical burden of disease in BCBM was investigated, as well as the role of aldehyde dehydrogenase 1A3 (ALDH1A3) in the metastatic cascade leading to BCBM development. Initial analysis of clinical survival trends for breast cancer and BCBM determined improvement of breast cancer survival rates; however, this has failed to positively affect the prognostic milestones of triple-negative breast cancer (TNBC) brain metastases (BM). ALDH1A3 and a representative epithelial-mesenchymal transition (EMT) gene signature (mesenchymal markers, CD44 or Vimentin) were compared in tumors derived from BM, lung metastases (LM), or bone metastases (BoM) of patients as well as mice after injection of TNBC cells. Selective elevation of the EMT signature and ALDH1A3 were observed in BM, unlike LM and BoM, especially in the tumor edge. Furthermore, ALDH1A3 was determined to play a role in BCBM establishment via regulation of circulating tumor cell adhesion and migration phases in the BCBM cascade. Validation through genetic and pharmacologic inhibition of ALDH1A3 via lentiviral shRNA knockdown and a novel small-molecule inhibitor demonstrated selective inhibition of BCBM formation with prolonged survival of tumor-bearing mice. Given the survival benefits via targeting ALDH1A3, it may prove an effective therapeutic strategy for BCBM prevention and/or treatment.
| S-EPMC7716183 | biostudies-literature
Project description:To determine the effect ALDH1A3 expression on global gene expression in MDA-MB-231 cells and MDA-MB-468 cells In MDA-MB-231 cells, ALDH1A3 was overexperssed (have low endogenous levels of ALDH1A3) and compared to MSCV empty vector control. In MDA-MB-468 cells that have high endogenous levels of ALDH1A3, ALDH1A3 expresion was reduced with ALDH1A3 shRNA1 and compared to scramble shRNA control.
2014-02-04 | E-GEOD-49322 | biostudies-arrayexpress
Project description:Gastric cancer (GC) stem cells (GCSCs) are characterized as high level of ALDH activity, however, the mechanisms of maintenance of high ALDH activity and stemness in GCSCs are largely unknown. Here, we report that KDM4C, a H3K9me2/3-demethylase, epigenetically regulates ALDH1A3 by histone demethylation and forms a feed-forward loop with ALDH1A3 to supports GS stemness. Ectopic expression of both KDM4C and ALDH1A3 promotes the properties of GCSCs, including spherogenecity, self-renewal, CD44 expression and ALDH activity; knockdown of anyone abolished the effect of each other. KDM4C directly binds to the promoter of ALDH1A3, leads to histone demethylation, thereby promoting ALDH1A3 transcription. Upregulated ALDH1A3 in turn transcriptionally upregulates KDM4C. Simultaneous inhibition of KDM4C and ALDH1A3 synergistically sensitizes GC sphere-derived cells to traditional chemotherapeutic drugs. The finding that upregulated ALDH1A3 promotes its own transcription via KDM4C-mediated epigenetic modification represents an important feed-forward mechanism for GCSCs to maintain stemness and promote tumourigenesis and our work thus suggests a novel therapeutic strategy for eradicating human GCSCs. To investigate the mechanisms underlying KDM4C promoting CG stemness, we identified the differentially expressed proteins (DEPs) between KDM4C-overexpressing and control AGS cells by iTRAQ-based quantitative proteomic analysis.
2022-02-16 | PXD023455 | Pride
Project description:Type 2 diabetes (T2D) is associated with defective insulin secretion, reduced β-cell mass, and β-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) serves as a marker of β-cell dedifferentiation and correlates with T2D progression. ALDH1A3-positive β-cells (A+) demonstrate impaired insulin secretion, and their numbers decrease when diabetic mice are rendered euglycemic by pair-feeding. It is unknown whether ALDH1A3 activity contributes to β-cell failure, and whether the decrease of A+ cells under pair-feeding is due to β-cell restoration. To tackle these questions, we (i) investigated the fate of A+ cells during pair-feeding by lineage-tracing, (ii) somatically ablated ALDH1A3 in diabetic β-cells, and (iii) used a novel selective ALDH1A3 inhibitor to treat diabetes. Lineage tracing and functional characterization show that A+ cells can be reconverted to functional, mature β-cells. Genetic or pharmacological inhibition of ALDH1A3 in diabetic mice lowers glycemia and increases insulin secretion. Molecular interrogation of β-cells following ALDH1A3 inhibition show a reactivation of differentiation as well as regeneration pathways through the REG gene family. We conclude that ALDH1A3 inhibition offers a therapeutic strategy for β-cell dysfunction in diabetes.
2023-01-09 | GSE218047 | GEO
Project description:Metabolic dependencies of metastasis-initiating cells in breast cancer
| PRJNA912211 | ENA
Project description:Cancer progression and therapy resistance arise from metabolic and transcriptional adaptations, but how these are interconnected is less well understood. We propose that in melanoma, the pan-cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) couples TFAP2B-neural crest stem cell gene transcription with a distinct acetyl-histone H3 landscape via its substrate acetaldehyde. Mechanistically, nuclear acetyl-CoA synthetase 2 (ACSS2) colocalises with ALDH1A3 to bind glucose metabolic and neural crest stem cell gene loci and promote local acetyl-histone H3 modification dependent on ALDH1A3. Consistent with clinical observations that dedifferentiation into stem cell states confer poor prognosis in melanoma patients and mediate drug resistance, we found in a zebrafish melanoma model that targeting the ALDH1A3-high subpopulation with an ALDH1 suicide inhibitor delayed BRAF inhibitor drug-resistant relapse. Our work identifies ALDH1A3 as a master coordinator of acetaldehyde metabolites that directly regulates chromatin-based gene regulation, and which can be pharmacologically targeted to improve therapeutic outcomes.
2024-06-29 | GSE243834 | GEO
Project description:Cancer progression and therapy resistance arise from metabolic and transcriptional adaptations, but how these are interconnected is less well understood. We propose that in melanoma, the pan-cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) couples TFAP2B-neural crest stem cell gene transcription with a distinct acetyl-histone H3 landscape via its substrate acetaldehyde. Mechanistically, nuclear acetyl-CoA synthetase 2 (ACSS2) colocalises with ALDH1A3 to bind glucose metabolic and neural crest stem cell gene loci and promote local acetyl-histone H3 modification dependent on ALDH1A3. Consistent with clinical observations that dedifferentiation into stem cell states confer poor prognosis in melanoma patients and mediate drug resistance, we found in a zebrafish melanoma model that targeting the ALDH1A3-high subpopulation with an ALDH1 suicide inhibitor delayed BRAF inhibitor drug-resistant relapse. Our work identifies ALDH1A3 as a master coordinator of acetaldehyde metabolites that directly regulates chromatin-based gene regulation, and which can be pharmacologically targeted to improve therapeutic outcomes.
2024-06-29 | GSE243840 | GEO
Project description:Background and aims: Cancer metastasis is the biggest obstacle to esophageal squamous cell carcinoma (ESCC) treatment. At present, understanding of its mechanism remains insufficient. Therefore, an in-depth exploration of the mechanisms of metastasis is crucial for early detection and intervention to reduce metastasis-related mortality. Methods: This study applied single-cell RNA sequencing analysis to investigate lung metastatic ESCC cells isolated from a pulmonary metastasis mouse model at multiple timepoints to characterize early metastatic microenvironment. Results: We identified a small population of parental ESCC KYSE30 cell line (Cluster S) resembled metastasis-initiating cells (MICs) because they could survive and colonize at lung metastatic sites. By comparing differential expression profiles between Cluster S and other subpopulations, we identified a panel of 7 metastasis-initiating signature genes (MIS), including CD44 and TACSTD2, to represent MICs of ESCC. Functional studies demonstrated that Cluster S cells (CD44high) exhibited significantly enhanced cell survival (resistances to oxidative stress and apoptosis), cell migration, invasion, stemness, and in vivo lung metastasis capabilities. Multiplex immunohistochemistry (mIHC) staining of 4 MISs (CD44, S100A14, RHOD, and TACSTD2) in ESCC cell lines and clinical samples found that differential MIS expression scores (dMISs) could predict lymph node metastasis, overall survival and risk of carcinothrombosis. GO and KEGG analyses revealed that CD44high cells were enriched in cell migration, organ development, stress responses, and neuron development, which might be related to the establishment of early metastatic microenvironment. Conclusion: This study identified CD44, S100A14, RHOD, and TACSTD2 as MISs to represent the MICs in ESCC populations and predict patient outcomes. Keywords: ESCC, metastasis-initiating cells, metastasis-initiating signatures, biomarker, scRNA-seq.
2024-08-21 | GSE249057 | GEO
Project description:Background and aims: Cancer metastasis is the biggest obstacle to esophageal squamous cell carcinoma (ESCC) treatment. At present, understanding of its mechanism remains insufficient. Therefore, an in-depth exploration of the mechanisms of metastasis is crucial for early detection and intervention to reduce metastasis-related mortality. Methods: This study applied single-cell RNA sequencing analysis to investigate lung metastatic ESCC cells isolated from a pulmonary metastasis mouse model at multiple timepoints to characterize early metastatic microenvironment. Results: We identified a small population of parental ESCC KYSE30 cell line (Cluster S) resembled metastasis-initiating cells (MICs) because they could survive and colonize at lung metastatic sites. By comparing differential expression profiles between Cluster S and other subpopulations, we identified a panel of 7 metastasis-initiating signature genes (MIS), including CD44 and TACSTD2, to represent MICs of ESCC. Functional studies demonstrated that Cluster S cells (CD44high) exhibited significantly enhanced cell survival (resistances to oxidative stress and apoptosis), cell migration, invasion, stemness, and in vivo lung metastasis capabilities. Multiplex immunohistochemistry (mIHC) staining of 4 MISs (CD44, S100A14, RHOD, and TACSTD2) in ESCC cell lines and clinical samples found that differential MIS expression scores (dMISs) could predict lymph node metastasis, overall survival and risk of carcinothrombosis. GO and KEGG analyses revealed that CD44high cells were enriched in cell migration, organ development, stress responses, and neuron development, which might be related to the establishment of early metastatic microenvironment. Conclusion: This study identified CD44, S100A14, RHOD, and TACSTD2 as MISs to represent the MICs in ESCC populations and predict patient outcomes. Keywords: ESCC, metastasis-initiating cells, metastasis-initiating signatures, biomarker, scRNA-seq.
2024-08-21 | GSE249056 | GEO