Detection of Chemotherapy-Resistant Pancreatic Cancer Using a Glycan Biomarker
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ABSTRACT:
PROVIDER: PRJNA611767 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11281325_1.fastq.gz | Fastqsanger.gz | |||
| SRR11281325_2.fastq.gz | Fastqsanger.gz | |||
| SRR11281326_1.fastq.gz | Fastqsanger.gz | |||
| SRR11281326_2.fastq.gz | Fastqsanger.gz | |||
| SRR11281327_1.fastq.gz | Fastqsanger.gz |
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Project description:A subset of pancreatic ductal adenocarcinomas (PDACs) is highly resistant to systemic chemotherapy, but no markers are available in clinical settings to identify this subset. We found that chemotherapy-resistant PDACs, but not chemotherapy-sensitive PDACs, express a glycan biomarker called sTRA. We confirmed the use of this marker to identify treatment-resistant PDAC in multiple systems: sets of 24 cell lines, 27 organoids, and isogenic cell lines; gene-expression signatures in primary tumors; tissue microarrays containing primary tumors; and blood plasma from cohorts of human subjects. These findings establish the use of tissue or plasma assays to identify the PDACs that are resistant to chemotherapy, which could improve the precision of systemic treatments and facilitate biomarker-guided trials targeting resistant PDAC.
2021-04-13 | GSE146722 | GEO
Project description:PurposeA subset of pancreatic ductal adenocarcinomas (PDACs) is highly resistant to systemic chemotherapy, but no markers are available in clinical settings to identify this subset. We hypothesized that a glycan biomarker for PDACs called sialylated tumor-related antigen (sTRA) could be used for this purpose.Experimental designWe tested for differences between PDACs classified by glycan expression in multiple systems: sets of cell lines, organoids, and isogenic cell lines; primary tumors; and blood plasma from human subjects.ResultsThe sTRA-expressing models tended to have stem-like gene expression and the capacity for mesenchymal differentiation, in contrast to the nonexpressing models. The sTRA cell lines also had significantly increased resistance to seven different chemotherapeutics commonly used against pancreatic cancer. Patients with primary tumors that were positive for a gene expression classifier for sTRA received no statistically significant benefit from adjuvant chemotherapy, in contrast to those negative for the signature. In another cohort, based on direct measurements of sTRA in tissue microarrays, the patients who were high in sTRA again had no statistically significant benefit from adjuvant chemotherapy. Furthermore, a blood plasma test for the sTRA glycan identified the PDACs that showed rapid relapse following neoadjuvant chemotherapy.ConclusionsThis research demonstrates that a glycan biomarker could have value to detect chemotherapy-resistant PDAC in clinical settings. This capability could aid in the development of stratified treatment plans and facilitate biomarker-guided trials targeting resistant PDAC.
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Project description:Typically diagnosed late, when systemic metastasis has already occurred, pancreatic ductal adenocarcinoma (PDAC) has one of the worst 5-year survival rates of any cancer type. For many patients with advanced disease, current chemotherapy regimens offer only modest benefit despite significant toxicity and surgical resection, the only treatment option with curative potential, is not possible. Therefore, while new treatments are much needed, diagnosing patients at an ‘earlier’ disease stage when surgery remains possible and the window of opportunity for treatment response is longer will be critical to improving patient outcomes. In this regard, the identification of biomarkers from biospecimens that can be easily sampled from patients remains the focus of considerable research, however success has not been forthcoming. Using a suite of novel genetically defined murine isogenic models of early PDAC, engineered using CRISPR-Cas9 gene editing, we sought to address whether loss-of-function mutations in common driver genes, and thus the genetic heterogeneity inherent to the disease, may represent an important confounding factor in the identification of a one-size-fits-all biomarker suitable for early detection. Focussing on the multi-omics analysis of blood, we show that both loss of Cdkn2a and / or Smad4 on the background of a KrasG12D Trp53-/- genotype has profound effects on the profile of differentially expressed RNA species including protein coding RNAs, lncRNAs, snoRNAs, scRNAs, snRNAs and miRNAs, and on plasma protein expression, when compared to both healthy controls and chemically induced pancreatitis. In addition, we find that loss of Smad4, a genomic event that occurs following progression from PanIN to PDAC, substantially limits the availability of blood biomarkers. These findings identify the need to move towards genotype-specific biomarker signatures and uncover a potential role for Smad4 loss in limiting opportunities for the early detection of pancreatic cancer.
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Project description:Typically diagnosed late, when systemic metastasis has already occurred, pancreatic ductal adenocarcinoma (PDAC) has one of the worst 5-year survival rates of any cancer type. For many patients with advanced disease, current chemotherapy regimens offer only modest benefit despite significant toxicity and surgical resection, the only treatment option with curative potential, is not possible. Therefore, while new treatments are much needed, diagnosing patients at an ‘earlier’ disease stage when surgery remains possible and the window of opportunity for treatment response is longer will be critical to improving patient outcomes. In this regard, the identification of biomarkers from biospecimens that can be easily sampled from patients remains the focus of considerable research, however success has not been forthcoming. Using a suite of novel genetically defined murine isogenic models of early PDAC, engineered using CRISPR-Cas9 gene editing, we sought to address whether loss-of-function mutations in common driver genes, and thus the genetic heterogeneity inherent to the disease, may represent an important confounding factor in the identification of a one-size-fits-all biomarker suitable for early detection. Focussing on the multi-omics analysis of blood, we show that both loss of Cdkn2a and / or Smad4 on the background of a KrasG12D Trp53-/- genotype has profound effects on the profile of differentially expressed RNA species including protein coding RNAs, lncRNAs, snoRNAs, scRNAs, snRNAs and miRNAs, and on plasma protein expression, when compared to both healthy controls and chemically induced pancreatitis. In addition, we find that loss of Smad4, a genomic event that occurs following progression from PanIN to PDAC, substantially limits the availability of blood biomarkers. These findings identify the need to move towards genotype-specific biomarker signatures and uncover a potential role for Smad4 loss in limiting opportunities for the early detection of pancreatic cancer.
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Project description:Gene expression changes in normal pancreatic ductal organoids were isolated from mice with inducible expression of the glycan, CA19-9.
2019-06-05 | GSE130854 | GEO
Project description:Pancreatic cancer is the fourth leading cause of cancer death. Lack of early detection technology for pancreatic cancer invariably leads to a typical clinical presentation of incurable disease at initial diagnosis. Oral fluid (saliva) meets the demand for non-invasive, accessible, and highly efficient diagnostic medium. The level of salivary analytes, such as mRNA and microflora, vary upon disease onset; thus possess valuable signatures for early detection and screening. In this study, we evaluated the performance and translational utilities of the salivary transcriptomic and microbial biomarkers for non-invasive detection of early pancreatic cancer. Two biomarker discovery technologies were used to profile transcriptome in saliva supernatant and microflora in saliva pellet. The Affymetrix Human Genome U133 Plus 2.0 Array was used to discover altered gene expression in saliva supernatant. The Human Oral Microbe Identification Microarray (HOMIM) was used to investigate microflora shift in saliva pellet. Biomarkers selected from both studies were subjected to an independent clinical validation using a cohort of 30 early pancreatic cancer, 30 chronic pancreatitis and 30 healthy matched-control saliva samples. Two panels of salivary biomarkers, including eleven mRNA biomarkers and two microbial biomarkers were discovered and validated for pancreatic cancer detection. The logistic regression model with the combination of three mRNA biomarkers (ACRV1, DMXL2 and DPM1) yielded a ROC-plot AUC value of 0.974 (95% CI, 0.896 to 0.997; P < 0.0001) with 93.3% sensitivity and 90% specificity in distinguishing pancreatic cancer patients from healthy subjects. The logistic regression model with the combination of two bacterial biomarkers (Neisseria elongata and Streptococcus mitis) yielded a ROC-plot AUC value of 0.895 (95% CI, 0.784 to 0.961; P < 0.0001) with 96.4% sensitivity and 82.1% specificity in distinguishing pancreatic cancer patients from healthy subjects. Importantly, the logistic regression model with the combination of four biomarkers (mRNA biomarkers, ACRV1, DMXL2 and DPM1; bacterial biomarker, S. mitis) could differentiate pancreatic cancer patients from all non-cancer subjects (chronic pancreatitis and healthy control), yielding a ROC-plot AUC value of 0.949 (95% CI, 0.877 to 0.985; P < 0.0001) with 92.9% sensitivity and 85.5% specificity. This study comprehensively compared the salivary transcriptome and microflora between pancreatic cancer and control subjects. We have discovered and validated eleven mRNA biomarkers and two microbial biomarkers for early detection of pancreatic cancer in saliva. The logistic regression model with four salivary biomarkers can detect pancreatic cancer specifically without the complication of chronic pancreatitis. This is the first report demonstrating the value of multiplex salivary biomarkers for the non-invasive detection of a high impact systemic cancer. Keywords: Salivary biomarker, pancreatic cancer, early detection, salivary transcriptome, salivary microflora This study, which was approved by the UCLA Institutional Review Board, started sample collection in February 2006 and ended in April 2008. It had a discovery and verification phase, followed by an independent validation phase. All patients with clinically diagnosed early or locally advanced pancreatic cancer, chronic pancreatitis and matched healthy control were recruited from the UCLA Medical Center. The controls were matched for gender, age, ethnicity and smoking history. We chose early and locally advanced pancreatic cancers because they were considered early stage diseases. All patients were recently diagnosed with primary disease, and had not received any prior treatment in the form of chemotherapy, radiotherapy, surgery, or alternative remedies. No subjects had a history of prior malignancy, immunodeficiency, autoimmune disorders, hepatitis, or HIV infection. Written informed consent was obtained from all patients who agreed to serve as saliva donors. Unstimulated saliva samples were collected and processed as previously described. The saliva bank of pancreatic disease at the UCLA Dental Research Institute has collected 283 saliva samples since 2006. Of these, 114 samples, from 42 pancreatic cancer patients, 30 chronic pancreatitis patients and 42 healthy control subjects, met the following eligibility criteria: the disease subjectsâ?? samples were obtained immediately after primary diagnosis from patients without evidence of metastasis; the saliva sample was free of blood (Table 1 in accompanying manuscript). Of the 114 samples, 12 pancreatic cancer samples and 12 healthy control samples were chosen for the discovery and verification phase. The transcriptomic approach profiled the saliva supernatant samples from 12 pancreatic cancer patients and 12 healthy control subjects using the Affymetrix Human Genome U133 Plus 2.0 Array platform.
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