Spatial proteo-transcriptomic profiling reveals the molecular landscape of borderline ovarian tumors and their invasive progression
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PROVIDER: PRJNA1220694 | ENA |
REPOSITORIES: ENA
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Project description:Epithelial serous borderline tumors (SBT) are non-invasive neoplastic ovarian lesions that may recur as chemo-resistant low-grade serous cancer (LGSC). While genetic alterations suggest a common origin, the transition from SBT to LGSC remains poorly understood. Here, we integrate cell-type resolved spatial proteomics and transcriptomics to elucidate the evolution from SBT to LGSC and its corresponding metastasis in both the stroma and the tumor. We show that the transition of SBT to LGSC occurs in the epithelial compartment through an intermediary stage with micropapillary features. LGSC overexpressed the c-Met receptor tyrosine kinase and several CNS-specific proteins. In the tumor microenvironment, interconnectivity between cancer and tumor cells and enzymes degrading a packed extracellular matrix suggests functional collaboration between various cells in the tumor organ. Integrating spatial transcriptomics and proteomics, we functionally validate 16 drug targets.
2025-06-25 | GSE289044 | GEO
Project description:Serous borderline tumors (SBT) are epithelial neoplastic lesions of the ovaries that commonly have a good prognosis. In 10-15% of cases, however, SBT will recur as low-grade serous cancer (LGSC), which is deeply invasive and responds poorly to current standard chemotherapy1,2,3. While genetic alterations suggest a common origin, the transition from SBT to LGSC remains poorly understood4. Here, we integrate spatial proteomics5 with spatial transcriptomics to elucidate the evolution from SBT to LGSC and its corresponding metastasis at the molecular level in both the stroma and the tumor. We show that the transition of SBT to LGSC occurs in the epithelial compartment through an intermediary stage with micropapillary features (SBT-MP), which involves a gradual increase in MAPK signaling. A distinct subset of proteins and transcripts was associated with the transition to invasive tumor growth, including the neuronal splicing factor NOVA2, which was limited to expression in LGSC and its corresponding metastasis. An integrative pathway analysis exposed aberrant molecular signaling of tumor cells supported by alterations in angiogenesis and inflammation in the tumor microenvironment. Integration of spatial transcriptomics and proteomics followed by knockdown of the most altered genes or pharmaceutical inhibition of the most relevant targets confirmed their functional significance in regulating key features of invasiveness. Combining cell-type resolved spatial proteomics and transcriptomics allowed us to elucidate the sequence of tumorigenesis from SBT to LGSC. The approach presented here is a blueprint to systematically elucidate mechanisms of tumorigenesis and find novel treatment strategies.
| S-EPMC10680885 | biostudies-literature
Project description:Women of reproductive age can develop serous borderline tumors (SBT) characterized by the uncontrolled growth of epithelial cells that do not invade the stroma. Despite a good prognosis after surgery, SBT may recur as low-grade serous cancer (LGSC), which is invasive and responds poorly to current standard chemotherapy. SBT and LGSC have overlapping genomic changes, but a putative transition sequence is poorly understood. Here, we employ Deep Visual Proteomics (DVP), a recently introduced single cell type specific spatial technology, to elucidate the evolution of this cancer at the molecular level. We show that the transition of SBT to LGSC occurs in the epithelial compartment through an intermediary stage with micropapillary features (SBT-MP) which involves a gradual increase in MAPK signaling. Proteomics identified several neuronal proteins, including the splicing factor NOVA2, that are exclusive to LGSC and its corresponding metastasis. In the stroma we observed major differences between non-invasive and invasive phenotypes. An acute inflammatory response was only found in SBT-MP. Spatial transcriptomics complemented the insights gained from proteomics, showing an increase in c-Met signaling, mRNA splicing in the epithelium, and HIF1α/angiogenesis in stroma between SBT and the more invasive phenotypes. Inhibiting the most prominently regulated pathways validated our results and suggested an FDA-approved FOLR1 inhibitor as a potential therapeutic strategy. Knockdown or inhibition of the top hits identified using spatial proteomics and transcriptomics confirmed their functional significance regulating migration and invasion. Combining spatial proteomics with transcriptomics is a promising approach to gaining mechanistic insights into tumor transformations and identifying novel treatment strategies.
2025-06-20 | PXD046354 | Pride
Project description:Epithelial ovarian cancer (EOC) are a heterogeneous collection of malignancies, each with their own developmental origins, clinical behavior and molecular profile. With less than 5% of EOC cases, mucinous ovarian carcinoma is a rare form with a poor prognosis with a 5-year survival of 11% for advanced stages (III/IV). Clinically, due to the large size and heterogeneity of mu-cinous tumors, Malignant forms are difficult to distinguish from Borderline (15%) and benign (80%) forms with a better prognosis. Improving their diagnosis is therefore a challenge with regard to the risk of under-treating a malignant form or of unnecessarily undertaking radical surgical excision. The involvement of microRNAs (miRNAs) in cancer and their potential as biomarkers of diagnosis are becoming increasingly recognized. In this study, miRNA expres-sion profiling generates using FFPE patient samples followed by qRT-PCR validation allows to identify 10 down-regulated and 5 up-regulated miRNAs between Malignant and Borderline tumors. To overcome issues linked to data normalization and to improve the accuracy of the results, a ratio analysis combining up-regulated and down-regulated miRNAs was used. Alt-hough 21/50 miRNA expression ratio were significantly different between Malignant and Bor-derline tumor samples, any ratio could perfectly discriminate the two groups. However, a combination of 14 miRNAs expression ratio (double ratio) showed high discriminatory poten-tial, with 100% of accuracy in distinguishing Malignant and Borderline ovarian tumors, and suggests that miRNAs may hold significant clinical potential as a diagnostic tool. Epithelial ovarian cancer (EOC) are a heterogeneous collection of malignancies, each with their own developmental origins, clinical behavior and molecular profile. With less than 5% of EOC cases, mucinous ovarian carcinoma is a rare form with a poor prognosis with a 5-year survival of 11% for advanced stages (III/IV). Clinically, due to the large size and heterogeneity of mu-cinous tumors, Malignant forms are difficult to distinguish from Borderline (15%) and benign (80%) forms with a better prognosis. Improving their diagnosis is therefore a challenge with regard to the risk of under-treating a malignant form or of unnecessarily undertaking radical surgical excision. The involvement of microRNAs (miRNAs) in cancer and their potential as biomarkers of diagnosis are becoming increasingly recognized. In this study, miRNA expres-sion profiling generates using FFPE patient samples followed by qRT-PCR validation allows to identify 10 down-regulated and 5 up-regulated miRNAs between Malignant and Borderline tumors. To overcome issues linked to data normalization and to improve the accuracy of the results, a ratio analysis combining up-regulated and down-regulated miRNAs was used. Alt-hough 21/50 miRNA expression ratio were significantly different between Malignant and Bor-derline tumor samples, any ratio could perfectly discriminate the two groups. However, a combination of 14 miRNAs expression ratio (double ratio) showed high discriminatory poten-tial, with 100% of accuracy in distinguishing Malignant and Borderline ovarian tumors, and suggests that miRNAs may hold significant clinical potential as a diagnostic tool.
2023-10-19 | GSE245725 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE39579: Proteo-Genomic Characterization and Mapping of Nucleosomes Decoded by Brd and HP1 Proteins (Chip-Seq data) GSE39580: Proteo-Genomic Characterization and Mapping of Nucleosomes Decoded by Brd and HP1 Proteins (expression data) Refer to individual Series
2012-07-30 | E-GEOD-39581 | biostudies-arrayexpress
Project description:Introduction: Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histological sub-type remains undetermined. While these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors. Methods: To explore the spectrum of genomic alterations common to mucinous tumors we performed high resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n=20) and borderline tumors (n=22). Results: Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors. Conclusions: This study is the largest and highest resolution analysis of mucinous benign and borderline tumors performed to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways. Copy number data was generated for 42 mucinous ovarian tumours (20 benign, 22 borderline). Epithelial and stromal DNA from the tumours and matched-normal lymphocyte DNA were all analysed. Processed/normalized data for the germline DNA samples are not provided because they themselves are normalised to a diploid copy number, making all the probe values 2, which is not informative.
2012-08-26 | E-GEOD-39076 | biostudies-arrayexpress
Project description:Introduction: Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histological sub-type remains undetermined. While these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors. Methods: To explore the spectrum of genomic alterations common to mucinous tumors we performed high resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n=20) and borderline tumors (n=22). Results: Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors. Conclusions: This study is the largest and highest resolution analysis of mucinous benign and borderline tumors performed to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways.
2012-08-26 | GSE39076 | GEO
Project description:The Diversity of Methylation Patterns in Serous Borderline Ovarian Tumors and Serous Ovarian Carcinomas
| PRJNA1109434 | ENA
Project description:Background: Changes in DNA methylation patterns are a pivotal mechanism of carcinogenesis. In some tumors, aberrant methylation precedes genetic changes, while gene expression may be more frequently modified due to methylation alterations than by mutations. Methods: Herein, 128 serous ovarian tumors were analyzed, including borderline ovarian tumors (BOTS) with (BOT.V600E) and without (BOT) the BRAF V600E mutation, low-grade (lg), and high-grade (hg) ovarian cancers (OvCa). The methylome of the samples was profiled with Infinium MethylationEPIC microarrays. Results: The biggest number of differentially methylated (DM) CpGs and regions (DMRs) was found between lgOvCa and hgOvCa. By contrast, the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups and, in relation to BOT, their genome was strongly downmethylated. Remarkably, the ten most significant DMRs, discriminating BOT from lgOvCa, encompassed the MHC region on chromosome 6. We also identified hundreds of DMRs, being of potential use as predictive biomarkers in BOTS and hgOvCa. DMRs with the best discriminative capabilities overlapped the following genes: BAIAP3, IL34, WNT10A, NEU1, SLC44A4, and HMOX1, TCN2, PES1, RP1-56J10.8, ABR, NCAM1, RP11-629G13.1, AC006372.4, NPTXR in BOTS and hgOvCa, respectively. Conclusions: The global genome-wide hypomethylation positively correlates with the increasing aggressiveness of ovarian tumors. We also assume that the immune system may play a pivotal role in the transition from BOTS to lgOvCa. Given that the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups, when methylome is considered, such tumors might be placed in-between BOT and OvCa.
2024-10-18 | GSE267068 | GEO
Project description:Low-grade serous ovarian carcinomas are typically Ras-pathway mutated, TP53 wild-type, have limited chromosomal aberration, and are frequently associated with borderline tumors. By contrast, high-grade serous ovarian carcinoma lack Ras-pathway mutations, are invariably TP53 mutated, show widespread genomic change, and are commonly BRCA-pathway disrupted. We sought to identify differences in genomic copy number changes in borderline and invasive components of serous carcinoma. Borderline and invasive tumor components were profiled from patients with LGSC
2014-10-01 | E-GEOD-57270 | biostudies-arrayexpress