The molecular and stromal landscape of salivary duct carcinoma reveals new therapeutic opportunities
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE138581 | GEO | 2020/02/12
REPOSITORIES: GEO
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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.
| S-EPMC7150470 | biostudies-literature
Project description:The molecular and stromal landscape of salivary duct carcinoma reveals new therapeutic opportunities
| PRJNA576455 | ENA
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:Salivary duct carcinoma (SDC) is a rare, aggressive salivary malignancy that is often diagnosed at an advanced stage. Previously, little was known about outcomes of this disease due to its rarity. In the past several years, much has been learned about salivary duct carcinoma after publication of outcomes from several large single-institution series and national database searches. Recent studies of genomic alterations have helped elucidate the biology and pathogenesis of this aggressive disease. Here we review outcomes of the disease, effects of treatment, prognostic factors, and genomic alterations in SDC. Studies of targeted therapy and promising future directions are also discussed.
| S-EPMC5685667 | biostudies-literature
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.
| S-EPMC5652672 | biostudies-literature
Project description:Mesenchymal stromal cells (MSCs) have been the subject of clinical trials for more than a generation, and the outcomes of advanced clinical trials have fallen short of expectations raised by encouraging pre-clinical animal data in a wide array of disease models. In this Perspective, important biological and pharmacological disparities in pre-clinical research and human translational studies are highlighted, and analyses of clinical trial failures and recent successes provide a rational pathway to MSC regulatory approval and deployment for disorders with unmet medical needs.
| S-EPMC6434696 | biostudies-literature
Project description:Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy, which often presents at an advanced stage. A proportion of SDC are characterized by HER2 amplification and/or overexpression of androgen receptor (AR), which could be targeted in a subset of patients, but the presence of AR splice variant-7 (AR-V7) in some SDC cases could result in resistance to anti-androgen therapy. We evaluated a cohort of 28 cases of SDC for potentially targetable biomarkers and pathways using immunohistochemistry (IHC) and next-generation sequencing (DNA and RNA) assays. Pathogenic genetic aberrations were found in all but 1 case and affected TP53 (n = 19), HRAS (n = 7), PIK3CA, ERBB2 (HER2), and NF1 (n = 5 each); KMT2C (MLL3) and PTEN (n = 3 each); BRAF (p.V600E), KDM5C and NOTCH1 (n = 2 each). Androgen receptor was expressed in all cases and 13 of 27 harbored the AR-V7 splice variant (including a case without any other detectable genetic alteration). HER2 IHC was expressed in 11 of 28 cases. The majority of SDC cases had no biomarkers predictive of immunotherapy response: 5 cases exhibited low (1%-8%) programmed death ligand 1 (PD-L1) expression in tumor cells, 2 cases exhibited elevated TMB, and no samples exhibited microsatellite instability. Notably, the pre-treatment biopsies from 2 patients with metastatic disease, who demonstrated clinical responses to anti-androgen therapy, showed AR expression and no AR splice variants. We conclude that comprehensive molecular profiling of SDCs can guide the selection of patients for targeted therapies involving AR, HER2, PD-L1, mitogen-activated protein kinase, and PIK3CA pathways.
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2023-09-27 | GSE233217 | GEO