Increased retinoic acid signalling decreases lung metastasis in salivary adenoid cystic carcinoma by inhibiting the noncanonical Notch1 pathway
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE216852 | GEO | 2023/03/09
REPOSITORIES: GEO
Similar Datasets
Project description:MYB-NFIB fusion and NOTCH1 mutation are hallmark genetic events familiar in SACC that promote lung metastasis. However, abnormal expression of MYB and NOTCH1 was also observed in without MYB-NFIB fusion and NOTCH1 mutation. Here, through single-cell RNA sequencing (scRNA-seq) and exome target capture sequencing in two SACC patients without MYB-NFIB fusion and NOTCH1 mutation, we explore in-depth the molecular mechanisms of lung metastasis. Twenty-five types of cells in primary and metastatic tissues were identified via Seurat clustering and categorized into four main stages ranging from near normal to cancer state based on the normal tissue occupancy for each cell cluster. In this context, we identified the Notch signalling pathway enrichment in almost all cancer cells; trajectory and sub-clustering analyses investigated deeply cancer progenitor-like cell clusters in primary tumour-associated lung metastases, in which signature genes enriched in the ‘MYC_TARGETS_V2’ gene set. In vitro, we detected the complexes of the NICD1-MYB-MYC by Co-immunoprecipitation (Co-IP) and incidentally identified retinoic acid (RA) signalling as endogenous antagonists of the ‘MYC_TARGETS_V2’ gene set. Following this, we validate that all-trans retinoic acid (ATRA) reduces the lung metastasis in SACC via correcting erroneous cell differentiation mainly caused by aberrant NOTCH1 or MYB expression. Bioinformatic and immunohistochemical (IHC) analyses of four primary tissues and eleven metastatic lung tissues from patients with SACC suggested that RA system insufficiency partially promotes lung metastasis. These findings imply the value of diagnosis and treatment of the RA system.
2023-03-09 | GSE216913 | GEO
Project description:MYB-NFIB fusion and NOTCH1 mutation are hallmark genetic events familiar in SACC that promote lung metastasis. However, abnormal expression of MYB and NOTCH1 was also observed in without MYB-NFIB fusion and NOTCH1 mutation. Here, through single-cell RNA sequencing (scRNA-seq) and exome target capture sequencing in two SACC patients without MYB-NFIB fusion and NOTCH1 mutation, we explore in-depth the molecular mechanisms of lung metastasis. Twenty-five types of cells in primary and metastatic tissues were identified via Seurat clustering and categorized into four main stages ranging from near normal to cancer state based on the normal tissue occupancy for each cell cluster. In this context, we identified the Notch signalling pathway enrichment in almost all cancer cells; trajectory and sub-clustering analyses investigated deeply cancer progenitor-like cell clusters in primary tumour-associated lung metastases, in which signature genes enriched in the ‘MYC_TARGETS_V2’ gene set. In vitro, we detected the complexes of the NICD1-MYB-MYC by Co-immunoprecipitation (Co-IP) and incidentally identified retinoic acid (RA) signalling as endogenous antagonists of the ‘MYC_TARGETS_V2’ gene set. Following this, we validate that all-trans retinoic acid (ATRA) reduces the lung metastasis in SACC via correcting erroneous cell differentiation mainly caused by aberrant NOTCH1 or MYB expression. Bioinformatic and immunohistochemical (IHC) analyses of four primary tissues and eleven metastatic lung tissues from patients with SACC suggested that RA system insufficiency partially promotes lung metastasis. These findings imply the value of diagnosis and treatment of the RA system.
2023-03-09 | GSE217082 | GEO
Project description:MYB-NFIB fusion and NOTCH1 mutation are hallmark genetic events familiar in SACC that promote lung metastasis. However, abnormal expression of MYB and NOTCH1 was also observed in without MYB-NFIB fusion and NOTCH1 mutation. Here, through single-cell RNA sequencing (scRNA-seq) and exome target capture sequencing in two SACC patients without MYB-NFIB fusion and NOTCH1 mutation, we explore in-depth the molecular mechanisms of lung metastasis. Twenty-five types of cells in primary and metastatic tissues were identified via Seurat clustering and categorized into four main stages ranging from near normal to cancer state based on the normal tissue occupancy for each cell cluster. In this context, we identified the Notch signalling pathway enrichment in almost all cancer cells; trajectory and sub-clustering analyses investigated deeply cancer progenitor-like cell clusters in primary tumour-associated lung metastases, in which signature genes enriched in the ‘MYC_TARGETS_V2’ gene set. In vitro, we detected the complexes of the NICD1-MYB-MYC by Co-immunoprecipitation (Co-IP) and incidentally identified retinoic acid (RA) signalling as endogenous antagonists of the ‘MYC_TARGETS_V2’ gene set. Following this, we validate that all-trans retinoic acid (ATRA) reduces the lung metastasis in SACC via correcting erroneous cell differentiation mainly caused by aberrant NOTCH1 or MYB expression. Bioinformatic and immunohistochemical (IHC) analyses of four primary tissues and eleven metastatic lung tissues from patients with SACC suggested that RA system insufficiency partially promotes lung metastasis. These findings imply the value of diagnosis and treatment of the RA system. Cells from fresh tumour tissues were isolated for the preparation of single-cell suspensions via the ChromiumTM Single Cell 3’ Solution technique and analysed by BioMiao Biological Technology (Beijing) Co., Ltd.
2023-03-09 | GSE217081 | GEO
Project description:MYB-NFIB fusion and NOTCH1 mutation are hallmark genetic events familiar in SACC that promote lung metastasis. However, abnormal expression of MYB and NOTCH1 was also observed in without MYB-NFIB fusion and NOTCH1 mutation. Here, through single-cell RNA sequencing (scRNA-seq) and exome target capture sequencing in two SACC patients without MYB-NFIB fusion and NOTCH1 mutation, we explore in-depth the molecular mechanisms of lung metastasis. Twenty-five types of cells in primary and metastatic tissues were identified via Seurat clustering and categorized into four main stages ranging from near normal to cancer state based on the normal tissue occupancy for each cell cluster. In this context, we identified the Notch signalling pathway enrichment in almost all cancer cells; trajectory and sub-clustering analyses investigated deeply cancer progenitor-like cell clusters in primary tumour-associated lung metastases, in which signature genes enriched in the ‘MYC_TARGETS_V2’ gene set. In vitro, we detected the complexes of the NICD1-MYB-MYC by Co-immunoprecipitation (Co-IP) and incidentally identified retinoic acid (RA) signalling as endogenous antagonists of the ‘MYC_TARGETS_V2’ gene set. Following this, we validate that all-trans retinoic acid (ATRA) reduces the lung metastasis in SACC via correcting erroneous cell differentiation mainly caused by aberrant NOTCH1 or MYB expression. Bioinformatic and immunohistochemical (IHC) analyses of four primary tissues and eleven metastatic lung tissues from patients with SACC suggested that RA system insufficiency partially promotes lung metastasis. These findings imply the value of diagnosis and treatment of the RA system.
2023-03-09 | GSE217084 | GEO
Project description:MYB-NFIB fusion and NOTCH1 mutation are hallmark genetic events familiar in SACC that promote lung metastasis. However, abnormal expression of MYB and NOTCH1 was also observed in without MYB-NFIB fusion and NOTCH1 mutation. Here, through single-cell RNA sequencing (scRNA-seq) and exome target capture sequencing in two SACC patients without MYB-NFIB fusion and NOTCH1 mutation, we explore in-depth the molecular mechanisms of lung metastasis. Twenty-five types of cells in primary and metastatic tissues were identified via Seurat clustering and categorized into four main stages ranging from near normal to cancer state based on the normal tissue occupancy for each cell cluster. In this context, we identified the Notch signalling pathway enrichment in almost all cancer cells; trajectory and sub-clustering analyses investigated deeply cancer progenitor-like cell clusters in primary tumour-associated lung metastases, in which signature genes enriched in the ‘MYC_TARGETS_V2’ gene set. In vitro, we detected the complexes of the NICD1-MYB-MYC by Co-immunoprecipitation (Co-IP) and incidentally identified retinoic acid (RA) signalling as endogenous antagonists of the ‘MYC_TARGETS_V2’ gene set. Following this, we validate that all-trans retinoic acid (ATRA) reduces the lung metastasis in SACC via correcting erroneous cell differentiation mainly caused by aberrant NOTCH1 or MYB expression. Bioinformatic and immunohistochemical (IHC) analyses of four primary tissues and eleven metastatic lung tissues from patients with SACC suggested that RA system insufficiency partially promotes lung metastasis. These findings imply the value of diagnosis and treatment of the RA system.
2023-03-09 | GSE217083 | GEO
Project description:BackgroundNumerous studies have reported both the tumor-suppressive and oncogenic roles of the Notch pathway, indicating that Notch activity regulates tumor biology in a complex, context-dependent manner. The aim of the present study was to identify the role of NOTCH1 in the cell growth and metastasis of SACC.MethodsWe analyzed the expression of NOTCH1 in clinical SACC samples using immunohistochemical staining. We silenced the expression of NOTCH1 and overexpressed activated NOTCH1 to elucidate the effects of NOTCH1 on proliferation, migration and invasion. NOTCH1 target genes were validated by real-time PCR.ResultsOur results showed that NOTCH1 was upregulated in SACC tissues when compared with normal tissues, and this upregulation was further enhanced in SACC tissues with metastasis and recurrence when compared with SACC tissues without metastasis. Overexpression of NOTCH1 in SACC cells promoted cell growth, migration and invasion, and knockdown of NOTCH1 inhibited cell proliferation in vitro and tumorigenicity in vivo by inducing cell apoptosis.ConclusionsThe results of this study suggest that NOTCH1 plays a key role in the cell growth, anti-apoptosis, and metastasis of SACC. NOTCH1 inhibitors might therefore have potential therapeutic applications in treating SACC patients by inhibiting cancer cell growth and metastasis.
| S-EPMC4196170 | biostudies-literature
Project description:CXCR5 played critical roles in tumorigenesis and metastasis. Nevertheless, little was known about the involvement of CXCR5 in perineural invasion (PNI) of salivary adenoid cystic carcinoma (SACC). Here, we confirmed upregulation of CXCR5 in SACC specimens and cells and identified that CXCR5 exhibited a significant positive correlation with PNI. Functionally, knockdown of CXCR5 suppressed SACC cells migration, invasion and PNI ability, whereas CXCR5 overexpression displayed the opposite effects. Moreover, CXCR5 downregulated microRNA (miR)-187, which could competitively sponge S100A4. The PNI-inhibitory effect of CXCR5 knockdown or miR-187 overexpression could be reversed by elevated expression of S100A4. Conjointly, our data revealed that CXCR5 facilitated PNI through downregulating miR-187 to disinhibit S100A4 expression in SACC.
| S-EPMC8221347 | biostudies-literature
Project description:Adenoid cystic carcinomas (ACC) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole-genome sequencing and expression and pathway analyses. In addition to the well-described MYB-NFIB fusion that was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor gene in seven tumors (28%). Taken together, NFIB translocations occurred in 15 of 25 samples (60%, 95% CI, 41%-77%). In addition, mRNA expression analysis of 17 tumors revealed overexpression of NFIB in ACC tumors compared with normal tissues (P = 0.002). There was no difference in NFIB mRNA expression in tumors with NFIB fusions compared with those without. We also report somatic mutations of genes involved in the axonal guidance and Rho family signaling pathways. Finally, we confirm previously described alterations in genes related to chromatin regulation and Notch signaling. Our findings suggest a separate role for NFIB in ACC oncogenesis and highlight important signaling pathways for future functional characterization and potential therapeutic targeting.
| S-EPMC4818686 | biostudies-literature
Project description:Salivary gland cancer is an aggressive and painful cancer, but a rare tumor type accounting for only ~0.5% of cancer cases. Tumors of the salivary gland exhibit heterogeneous histologic and genetic features and they are subdivided into different subtypes, with adenoid cystic carcinomas (ACC) being one of the most abundant. Treatment of ACC patients is afflicted by high recurrence rates, the high potential of the tumors to metastasize, as well as the poor response of ACC to chemotherapy. A prerequisite for the development of targeted therapies is insightful genetic information for driver core cancer pathways. Here, we developed a transgenic mouse model toward establishment of a preclinical model. There is currently no available mouse model for adenoid cystic carcinomas as a rare disease entity to serve as a test system to block salivary gland tumors with targeted therapy. Based on tumor genomic data of ACC patients, a key role for the activation of the PI3K-AKT-mTOR pathway was suggested in tumors of secretory glands. Therefore, we investigated the role of Akt3 expression in tumorigenesis and report that Akt3 overexpression results in ACC of salivary glands with 100% penetrance, while abrogation of transgenic Akt3 expression could revert the phenotype. In summary, our findings validate a novel mouse model to study ACC and highlight the druggable potential of AKT3 in the treatment of salivary gland patients.
| S-EPMC5806106 | biostudies-literature
Project description:Salivary adenoid cystic carcinoma (SACC) is a peculiar malignant tumor, characterized by its slow but inexorable growth, with a high incidence of lung metastasis and poor prognosis. Here, we show the upregulated expression of EGFR ligand epiregulin in a subset of SACC cells correlates with lung metastasis and unfavorable outcome in patients with SACC. We found that upregulation of epiregulin in SACC cells induced epithelial-mesenchymal transition by regulating GLI1/E-cadherin. Elevated epiregulin increased the expression of pro-angiogenic factors, such as VEGFA, bFGF, and IL-8. We also show that epiregulin can be delivered via exosomes and was enriched in exosomes derived from epiregulin-overexpressing SACC cells. Furthermore, treating immunodeficient mice with these epiregulin-enriched exosomes greatly enhanced SACC metastasis to lung. These epiregulin-enriched exosomes significantly enhanced angiogenesis in the neighboring tumor microenvironment and increased vascular permeability in the pre-metastatic lung microenvironment in vivo. Therefore, epiregulin, as well as epiregulin-containing exosomes, may be a novel target for controlling SACC lung metastasis.
| S-EPMC5667342 | biostudies-other