The molecular and stromal landscape of salivary duct carcinoma reveals new therapeutic opportunities
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ABSTRACT:
PROVIDER: PRJNA576455 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10246409_1.fastq.gz | Fastqsanger.gz | |||
| SRR10246409_2.fastq.gz | Fastqsanger.gz | |||
| SRR10246410_1.fastq.gz | Fastqsanger.gz | |||
| SRR10246410_2.fastq.gz | Fastqsanger.gz | |||
| SRR10246411_1.fastq.gz | Fastqsanger.gz |
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Project description:Salivary duct carcinoma is a rare and aggressive salivary gland cancer subtype with poor prognosis. Its mutational landscape has been described rather exhaustively but little is known regarding its functional genomics and tumor microenvironment. In this study, we combined transcriptomics and proteomics to obtain a first characterization of deregulated pathways, which revealed the importance of Notch, TGB-β, and interferon-γ signaling. We then associated computational biology, immunohistochemistry, multiplexed immunofluorescence, and digital imaging to start charting the cellular network within the microenvironment, identify two well-defined groups of tumors according to their immune infiltrate, find novel SDC immune checkpoints, and show the role macrophages and NK cells in immunosuppression. Furthermore, we showed a clear trend between recurrence free survival and M2 macrophage abundance, and, independently, α-SMA abundance – a measure of desmoplastic stromal reaction. Altogether, these many findings open new perspectives for SDC. Classical patient stratification according to the immune infiltrate should be applied before choosing an immunotherapy. The microenvironment offers new actionable targets such as macrophages or NK cells, or even fibroblasts or hyaluronic acid in the absence of immune infiltrate. Related therapies are developed e.g. against pancreatic tumors that could inspire equivalents for SDC. Combinations with drugs targeting SDC mutated genes might also contribute to patient-specific regimens.
2020-05-26 | PXD015885 | Pride
Project description:Purpose: RNA-sequencing data was used to determine the main molecular pathways invovled in SDC and describe the tumoral microenvironment composition with key cellular networks within the latter.
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Project description:Salivary glands that produce and secret saliva, which is essential for lubrication, digestion, immunity, and oral homeostasis, consist of diverse cells. The long-term maintenance of diverse salivary gland cells in organoids remains problematic. Here, we established long-term murine salivary gland organoids from 3 major salivary glands, including parotid gland (PG), submandibular gland (SMG), and sublingual gland (SLG). Murine salivary gland organoids expressed gland-specific genes and proteins of acinar, myoepithelial, and duct cells. Organoids were maintained in growth media (named GEM) and further underwent differentiation in differentiation media (named DAM). Our study will provide an experimental platform for the exploration of mechanisms involvled in tissue regeneration, development, or several salivary gland diseases.
2022-05-05 | GSE184091 | GEO
Project description:Purpose: Salivary duct carcinoma (SDC) is a rare and aggressive salivary gland cancer subtype with poor prognosis. The mutational landscape of SDC has already been the object of several studies, however little is known regarding the functional genomics and the tumor microenvironment despite their importance in oncology. Our investigation aimed at describing both the functional genomics of SDC and the SDC microenvironment, along with their clinical relevance. Methods: RNA-sequencing (24 tumors), proteomics (17 tumors), immunohistochemistry (22 tumors), and multiplexed immunofluorescence (3 tumors) data were obtained from three different patient cohorts and analyzed by digital imaging and bioinformatics. Adjacent non-tumoral tissue from patients in two cohorts were used in transcriptomic and proteomic analyses. Results: Transcriptomic and proteomic data revealed the importance of Notch, TGF-?, and interferon-? signaling for all SDCs. We confirmed an overall strong desmoplastic reaction by measuring ?-SMA abundance, the level of which was associated with recurrence-free survival (RFS). Two distinct immune phenotypes were observed: immune-poor SDCs (36%) and immune-infiltrated SDCs (64%). Advanced bioinformatics analysis of the transcriptomic data suggested 72 ligand-receptor interactions occurred in the microenvironment and correlated with the immune phenotype. Among these interactions, three immune checkpoints were validated by immunofluorescence, including CTLA-4/DC86 and TIM-3/galectin-9 interactions, previously unidentified in SDC. Immunofluorescence analysis also confirmed an important immunosuppressive role of macrophages and NK cells, also supported by the transcriptomic data. Conclusions: Together our data significantly increase the understanding of SDC biology and open new perspectives for SDC tumor treatment. Before applying immunotherapy, patient stratification according to the immune infiltrate should be taken into account. Immune-infiltrated SDC could benefit from immune checkpoint-targeting therapy, with novel options such as anti-CTLA-4. Macrophages or NK cells could also be targeted. The dense stroma, i.e., fibroblasts or hyaluronic acid, may also be the focus for immune-poor SDC therapies, e.g. in combination with Notch or TGF-? inhibitors, or molecules targeting SDC mutations.
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Project description:Salivary glands that produce and secret saliva, which is essential for lubrication, digestion, immunity, and oral homeostasis, consist of diverse cells. Maintenance of diverse salivary gland cells in organoids remains problematic. Here, we established human salivary gland organoids, which is composed of multiple cellular subsets, from 3 major salivary glands, including parotid gland (PG), submandibular gland (SMG), and sublingual gland (SLG). Human salivary gland organoids expressed gland-specific genes and proteins of acinar, myoepithelial, and duct cells. Organoids were maintained in growth media (named GEM) and further underwent differentiation in differentiation media (named DAM). Our study will provide an experimental platform for the exploration of mechanisms involvled in tissue regeneration, development, or several salivary gland diseases.
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Project description:We established patient-derived organoids and monolayer culture cells from the salivary gland cancer cases. To compare the RNA profiles of primary culture cells (Organoids and monolayer culture cells) and their parental tumors, we isolated total RNA from 2 cases of the salivary gland cancer and performed transcriptome sequencing for the organoids, monolayer culture cells, and their parental tumors of both cases. Case 6 is a case of adenoid cystic carcinoma and Case 11 is a case of salivary duct carcinoma.
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Project description:Purpose: Use scRNA Seq to find stromal subpopulations and define how these subpopulations contribute to salivary gland proacinar differentiation. Method: scRNA Seq on stromal enriched cells from E16 salivary organoids. Model closely related cells using PCA and UMAP regressions. Find genes that broadly and specifically define cell subpopulations. Results: The stromal fibroblasts have multiple subpopulations. Stromal cells can be subdivided by their expression of Pdgfra, Pdgfrb, Thy1, and Acta2. Conclusions: Organoids grown with FGF2 selects for Pdgfra expressing stroma and without FGF2 Acta2 stroma dominates.
2022-03-01 | GSE193041 | GEO
Project description:Purpose: Use scRNA Seq to find B10stromal subpopulations and define how these subpopulations contribute to salivary gland proacinar differentiation. Method: scRNA Seq on stromal enriched cells from E16 salivary glands. Model closely related cells using PCA and UMAP regressions. Find genes that broadly and specifically define cell subpopulations. Results: The epithelium and stromal fibroblasts have multiple subpopulations. Stromal cells can be subdivided by their expression of Pdgfra, Pdgfrb, Thy1, Wnt2, and Acta2. Conclusions: Pdgfra expressing stroma specifically use BMP7 to promote proacinar differentiation.
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Project description:We performed directed differentiation of human pluripotent stem cells (hPSCs) into ureteric bud (UB) organoids and performed single cell transcriptomics to analyze different stages of development. At day 7, the spheroids exhibited a nephric duct (ND) signature, and we identified there is also a population of stromal progenitor cells within the cluster. At day 18, the organoids comprise more differentiated collecting duct (CD) cell types including principal cells.
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Project description:Salivary duct carcinomas (SDCa) are rare highly aggressive malignancies. Most patients die from distant metastatic disease within three years of diagnosis. There are limited therapeutic options for disseminated disease.11 cases showed androgen receptor expression and 6 cases showed HER2 amplification. 6 Somatic mutations with additional available targeted therapies were identified: EGFR (p.G721A: Gefitinib), PDGFRA (p.H845Y: Imatinib and Crenolanib), PIK3CA (p.H1047R: Everolimus), ERBB2 (p.V842I: Lapatinib), HRAS (p.Q61R: Selumetinib) and KIT (p.T670I: Sorafenib). Furthermore, alterations in PTEN, PIK3CA and HRAS that alter response to androgen deprivation therapy and HER2 inhibition were also seen.Somatic mutation analysis was performed on DNA extracted from 15 archival cases of SDCa using the targeted Illumina TruSeq Amplicon Cancer Panel. Potential targetable genetic alterations were identified using extensive literature and international somatic mutation database (COSMIC, KEGG) search. Immunohistochemistry for androgen receptor and immunohistochemistry and fluorescent in situ hybridization for HER2 were also performed.SDCa show multiple somatic mutations, some that are amenable to pharmacologic manipulation and others that confer resistance to treatments currently under investigation. These findings emphasize the need to develop testing and treatment strategies for SDCa.
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