FXYD5 (dysadherin) upregulation predicts shorter survival and reveals platinum resistance in high-grade serous ovarian cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE131978 | GEO | 2019/11/14
REPOSITORIES: GEO
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Project description:BackgroundHigh-grade serous ovarian carcinoma (HGSOC) is generally associated with a very dismal prognosis. Nevertheless, patients with similar clinicopathological characteristics can have markedly different clinical outcomes. Our aim was the identification of novel molecular determinants influencing survival.MethodsGene expression profiles of extreme HGSOC survivors (training set) were obtained by microarray. Differentially expressed genes (DEGs) and enriched signalling pathways were determined. A prognostic signature was generated and validated on curatedOvarianData database through a meta-analysis approach. The best prognostic biomarker from the signature was confirmed by RT-qPCR and by immunohistochemistry on an independent validation set. Cox regression model was chosen for survival analysis.ResultsEighty DEGs and the extracellular matrix-receptor (ECM-receptor) interaction pathway were associated to extreme survival. A 10-gene prognostic signature able to correctly classify patients with 98% of accuracy was identified. By an 'in-silico' meta-analysis, overexpression of FXYD domain-containing ion transport regulator 5 (FXYD5), also known as dysadherin, was confirmed in HGSOC short-term survivors compared to long-term ones. Its prognostic and predictive power was then successfully validated, both at mRNA and protein level, first on training than on validation sample set.ConclusionWe demonstrated the possible involvement of FXYD5 and ECM-receptor interaction signal pathway in HCSOC survival and prognosis.
| S-EPMC6889357 | biostudies-literature
Project description:We conducted single-cell RNA sequencing (scRNAseq) of tumor-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies to identify potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identified NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs and these were validated at the protein level. STAB1 inhibition in vitro induced anti-tumor macrophages. FOXP3 anti-sense oligonucleotide (FOXP3-ASO), repolarised Tregs to an effector T cell phenotype. ScRNAseq on 69,781 cells from an HGSOC syngeneic mouse model recapitulated the patients’ data. Combining chemotherapy with anti-stabilin1 antibody and/or Foxp3-ASO significantly increased survival of mice with established peritoneal disease in two HGSOC syngeneic models and progression-free survival in a third model. Long-term survivors (300 days+) were resistant to tumor rechallenge. Anti-stabilin1 antibody enriched the tumors with CXCL9+ macrophages and Foxp3-ASO increased TBET cell infiltration. Our results suggest targeting these molecules may improve chemotherapy response in patients.
2024-10-13 | GSE224091 | GEO
Project description:We conducted single-cell RNA sequencing (scRNAseq) of tumor-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies to identify potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identified NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs and these were validated at the protein level. STAB1 inhibition in vitro induced anti-tumor macrophages. FOXP3 anti-sense oligonucleotide (FOXP3-ASO), repolarised Tregs to an effector T cell phenotype. ScRNAseq on 69,781 cells from an HGSOC syngeneic mouse model recapitulated the patients’ data. Combining chemotherapy with anti-stabilin1 antibody and/or Foxp3-ASO significantly increased survival of mice with established peritoneal disease in two HGSOC syngeneic models and progression-free survival in a third model. Long-term survivors (300 days+) were resistant to tumor rechallenge. Anti-stabilin1 antibody enriched the tumors with CXCL9+ macrophages and Foxp3-ASO increased TBET cell infiltration. Our results suggest targeting these molecules may improve chemotherapy response in patients.
2024-10-11 | GSE224392 | GEO
Project description:We conducted single-cell RNA sequencing (scRNAseq) of tumor-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies to identify potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identified NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs and these were validated at the protein level. STAB1 inhibition in vitro induced anti-tumor macrophages. FOXP3 anti-sense oligonucleotide (FOXP3-ASO), repolarised Tregs to an effector T cell phenotype. ScRNAseq on 69,781 cells from an HGSOC syngeneic mouse model recapitulated the patients’ data. Combining chemotherapy with anti-stabilin1 antibody and/or Foxp3-ASO significantly increased survival of mice with established peritoneal disease in two HGSOC syngeneic models and progression-free survival in a third model. Long-term survivors (300 days+) were resistant to tumor rechallenge. Anti-stabilin1 antibody enriched the tumors with CXCL9+ macrophages and Foxp3-ASO increased TBET cell infiltration. Our results suggest targeting these molecules may improve chemotherapy response in patients.
2024-10-11 | GSE224389 | GEO
Project description:FXYD5 (dysadherin) upregulation predicts shorter survival and reveals platinum resistance in high-grade serous ovarian cancer
| PRJNA545492 | ENA
Project description:Platinum-based chemotherapies are widely used anti-cancer drugs. Tumor resistance to platinum compounds is a major determinant of patient survival, including in high grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential therapeutic targets in resistant HGSOC, we generated a comprehensive, reproducible data resource comprised of dynamic (+/-carboplatin) proteomic/posttranslational modification and RNASeq profiles from HGSOC intra-patient cell line pairs derived from 3 patients before and after acquiring platinum resistance. The molecular profiles revealed extensive responses to carboplatin and differential responses between sensitive and resistant cells. Higher oxidative phosphorylation and fatty acid oxidation (FAO) pathway expression were observed in the platinum-resistant cells, which was further validated in patient-derived xenograft (PDX) models. We show that both pharmacologic inhibition and CRISPR knockout of CPT1A, which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. Thus, FAO is a candidate therapeutic target to overcome platinum resistance.
2022-01-04 | GSE163152 | GEO
Project description:Background: Despite an early response to platinum-based chemotherapy in advanced stage high-grade serous ovarian cancer (HGSOC), the majority of patients will relapse with drug-resistant disease. Aberrant epigenetic alterations like DNA methylation are common in HGSOC. Differences in DNA methylation are associated with chemoresponse in these patients. The objective of this study was to identify and validate novel epigenetic markers of chemoresponse using genome-wide analysis of DNA methylation in extreme chemoresponsive HGSOC patients. Methods: Genome-wide next-generation sequencing was performed on methylation-enriched tumor DNA of two HGSOC patient groups with residual disease, extreme responders (≥18 months progression-free survival (PFS), n = 8) and non-responders (≤6 months PFS, n = 10) to platinum-based chemotherapy. DNA methylation and expression data of the same patients were integrated to create a gene list. Genes were validated on an independent cohort of extreme responders (n = 21) and non-responders (n = 31) using pyrosequencing and qRT-PCR. In-silico validation was performed using publicly available DNA methylation (n = 91) and expression (n = 208) datasets of unselected advanced stage HGSOC patients. Functional validation of FZD10 on chemosensitivity was done in ovarian cancer cell lines using siRNA-mediated silencing. Results: Integrated genome-wide methylome and expression analysis identified 45 significantly differentially methylated and expressed genes between two chemoresponse groups. Four genes FZD10, FAM83A, MYO18B and MKX were successfully validated in an external set of extreme chemoresponsive HGSOC patients. High FZD10 and MKX methylation was related with extreme responders and high FAM83 and MYO18B methylation with extreme non-responders. In publicly available advanced stage HGSOC datasets, FZD10, MYO18B and MKX methylation levels were associated with PFS. High FZD10 methylation was strongly associated with improved PFS [HR=0.43, 95%CI=0.27-0.65, p=0.0002]. Consistently, low FZD10 expression was associated with improved PFS [HR=1.36, 95%CI=0.99-1.88, p=0.058]. FZD10 silencing caused significant sensitization towards cisplatin treatment in survival assays and apoptosis assays. Conclusions: By applying genome-wide integrated methylome analysis on extreme chemoresponsive HGSOC patients, we identified novel clinically relevant, epigenetically-regulated markers of platinum-sensitivity in HGSOC patients. The clinical potential of these markers in predictive and therapeutic approaches has to be further validated in prospective studies.
2017-08-17 | GSE97128 | GEO
Project description:Introduction: Although High Grade Serous Ovarian Cancer (HGSOC) is considered a chemo-responsive disease, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival of <6 months. Validated biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of resistance. Methods: Differential DNA methylation was investigated in independent tumour sets using Illumina 27K HumanMethylation arrays and validated by bisulphite pyrosequencing. Gene expression was by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction into ovarian cancer cell lines. Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in HGSOC which recur by 6 months compared to after 12 months and/or with RECIST response (p<0.05, q<0.05). A decrease in methylation at these intragenic CpG sites was significantly correlated with decreased MSX1 gene expression. Low expression of MSX1 was associated with poor progression-free survival independent of known clinical prognostic features (p=0.014). Three mutant or wild-type TP53 expressing ovarian cancer cell lines, resistant to cisplatin, have reduced MSX1 expression compared to matched parental, platinum sensitive, lines. Re-expression of MSX1 in resistant lines led to cisplatin sensitisation, increased apoptosis, increased p21 and BAX expression. However, in two TP53-null cell lines, MSX1 failed to change cisplatin sensitivity. Conclusion: Hypomethylation of MSX1 is a biomarker of resistant HGSOC disease at presentation and identifies a novel mechanism of platinum drug resistance. Bisulphite converted DNA from the 86 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
2015-11-26 | E-GEOD-75414 | biostudies-arrayexpress
Project description:Ovarian cancer is the most frequent cause of death among gynecologic malignancies. A total of 80% of patients who have completed platinum-based chemotherapy suffer from relapse and develop resistance within 2 years. In the present study, we obtained patients' complete platinum (cisplatin and carboplatin) medication information from The Cancer Genome Atlas database and then divided them into two categories: resistance and sensitivity. Difference analysis was performed to screen differentially expressed genes (DEgenes) related to platinum response. Subsequently, we annotated DEgenes into the protein-protein interaction network as seed nodes and analyzed them by random walk. Finally, second-ranking protease serine 1 gene (PRSS1) was selected as a candidate gene for verification analysis. PRSS1's expression pattern was continuously studied in Oncomine and cBio Cancer Genomic Portal databases, revealing the key roles of PRSS1 in ovarian cancer formation. Hereafter, we conducted in-depth explorations on PRSS1's platinum response to ovarian cancer through tissue and cytological experiments. Quantitative real-time polymerase chain reaction and Western blot assay results indicated that PRSS1 expression levels in platinum-resistant samples (tissue/cell) were significantly higher than in samples sensitive to platinum. By cell transfection assay, we observed that knockdown of PRSS1 reduced the resistance of ovarian cancer cells to cisplatin. Meanwhile, overexpression of PRSS1 increased the resistance to cisplatin. In conclusion, we identified a novel risk gene PRSS1 related to ovarian cancer platinum response and confirmed its key roles using multiple levels of low-throughput experiments, revealing a new treatment strategy based on a novel target factor for overcoming cisplatin resistance in ovarian cancer.
| S-EPMC7876278 | biostudies-literature
Project description:High-grade serous ovarian cancer (HGSOC) progresses to advanced stages without symptoms and the 5-year survival rate is a dismal 30%. Recent studies of ovaries and oviducts in patients with BRCA mutations revealed that premalignant HGSC is found almost exclusively in the fallopian tube. To validate this notion, we cloned and transformed the fallopian tube stem cells (FTSC). We demonstrated that the tumors derived from the transformed fallopian tube stem cells (FTSCt) share the similar histological and molecular feature of high-grade serous cancer. In addition, a whole-genome transcriptome analysis comparing between FTSC, immortalized fallopian tube stem cells (FTSCi), and FTSCt showing a clear molecular progression, which is mimicked by the gene expression comparison between laser captured normal oviducts and HGSOC ( cancer and paired normal samples from 10 patients).
2015-09-29 | GSE69428 | GEO