Background: Neoadjuvant chemotherapy (NAC) has been of recent interest as an alternative to upfront surgery followed by adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). However, a subset of patients does not respond to NAC and may have been better managed by upfront surgery. Hence, there is an unmet need for accurate biomarkers for predicting NAC response in PDAC. We aimed to identify upregulated proteins in tumor tissue from poor- and good-NAC responders. Methods: Tumor and adjacent pancreas tissue samples were obtained following surgical resection from NAC-treated PDAC patients. SWATH-MS proteomic analysis was performed to identify and quantify proteins in tissue samples. Statistical analysis was performed to identify biomarkers for NAC response. Pathway analysis was performed to characterize affected canonical pathways in good- and poor-NAC responders. Results: A total of 3,156 proteins were identified, with 19 being were significantly upregulated in poor-responders compared to good-responders (log2 ratio > 2, p < 0.05). Those with the greatest ability to predict poor-NAC response were GRP78, CADM1, PGES2, and RUXF. Notably, canonical pathways that were significantly upregulated in good-responders included acute phase signaling and macrophage activation, indicating a heightened immune response in these patients. Conclusion: A novel biomarker signature for poor-NAC response in PDAC was identified.

/pdf/identification-of-novel-biomarkers-in-pancreatic-tumor-haiazflb1l.pdf

Identification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant Chemotherapy.

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal-around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients.

https://www.mdpi.com/2072-6694/11/8/1052/pdf

Omics Approaches in Pancreatic Adenocarcinoma.

Lipids are ubiquitous molecules, known to play important roles in various cellular processes. Alterations to the lipidome can therefore be used as a read-out of the signs of disease, highlighting the importance to consider lipids as biomarkers in addition of nucleic acid and proteins. Lipids are among the primary structural and functional constituents of biological tissues, especially cell membranes. Along with membrane formation, lipids play also a crucial role in cell signalling, inflammation and energy storage. It was shown recently that lipid metabolism disorders play an important role in carcinogenesis and development. As well, the role of lipids in disease is particularly relevant for bacterial infections, during which several lipid bacterial virulence factors are recognized by the human innate immune response, such as lipopolysaccharide in Gram-negative bacteria, lipoteichoic acid in Gram-positive bacteria, and lipoglycans in mycobacteria. Compared to nucleic acids and proteins, a complete analysis of the lipidome, which is the comprehensive characterization of different lipid families, is usually very challenging due to the heterogeneity of lipid classes and their intrinsic physicoproperties caused by variations in the constituents of each class. Understanding the chemical diversity of lipids is therefore crucial to understanding their biological relevance and, as a consequence, their use as potential biomarkers for non-infectious and infectious diseases. This mini-review exposes the current knowledge and limitations of the use of lipids as biomarkers of the top global killers which are cancer and bacterial infections.

Lipids as Biomarkers of Cancer and Bacterial Infections.

The incidence of patients with pancreatic cystic lesions, particularly intraductal papillary mucinous neoplasm (IPMN), is increasing. Current guidelines, which primarily consider radiological features and laboratory data, have had limited success in predicting malignant IPMN. The lack of a definitive diagnostic method has led to low-risk IPMN patients undergoing unnecessary surgeries. To address this issue, we discovered IPMN marker candidates by analyzing pancreatic cystic fluid by mass spectrometry. A total of 30 cyst fluid samples, comprising IPMN dysplasia and other cystic lesions, were evaluated. Mucus was removed by brief sonication, and the resulting supernatant was subjected to filter-aided sample preparation and high-pH peptide fractionation. Subsequently, the samples were analyzed by LC-MS/MS. Using several bioinformatics tools, such as gene ontology and ingenuity pathway analysis, we detailed IPMNs at the molecular level. Among the 5834 proteins identified in our dataset, 364 proteins were differentially expressed between IPMN dysplasia. The 19 final candidates consistently increased or decreased with greater IPMN malignancy. CD55 was validated in an independent cohort by ELISA, Western blot, and IHC, and the results were consistent with the MS data. In summary, we have determined the characteristics of pancreatic cyst fluid proteins and discovered potential biomarkers for IPMN dysplasia.

https://www.mdpi.com/2072-6694/12/9/2383/pdf

Marker identification of the grade of dysplasia of intraductal papillary mucinous neoplasm in pancreatic cyst fluid by quantitative proteomic profiling

Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with poor prognosis and rising incidence worldwide. Late detection and particularly aggressive characteristics are the major challenges that lead to therapeutic failure of this disease. A well described gene program and core regulators are yet to be discovered to drive the metastasis of the PDAC cells. As the development of single cell omics technologies including single cell RNA-sequencing (scRNA-seq), detailed characterization of the cellular composition of solid tumors and their microenvironments are well elaborated. In the current study, we accessed a recently published scRNA-seq dataset on primary and metastatic PDAC tissues and subset the tumor cells. By comparative analysis, we profiled the differentially expressed gene programs of primary and metastatic PDAC and found several long intergenic non-coding RNAs (LincRNAs) in top genes. The PDAC cancer cells showed some heterogeneity and were divided into four major subclusters based on gene profiles, one of which was mostly contributed by metastatic PDAC. Interestingly, this subcluster was remarkably marked by one of the above LincRNAs, MEG3, and exhibited significantly increased Epithelial-Mesenchymal-Transition (EMT) signatures. Ingenuity Pathway Analysis (IPA) on the signature genes of this subcluster gave multiple cancer metastasis associated and EMT signaling pathways, suggesting a critical role of this cluster in leading tumor cell metastasis. Taken together, this study displayed a PDAC cancer subcluster and its marker gene, biologically targeting of which might significantly attenuate the metastasis of tumor and might be a potential strategy for the therapeutic treatment of cancer.

/pdf/a-cancer-cell-cluster-marked-by-lincrna-meg3-leads-27x7in4c5d.pdf

A Cancer Cell Cluster Marked by LincRNA MEG3 Leads Pancreatic Ductal Adenocarcinoma Metastasis

Label-Free Quantitative Proteomics Unravels Carboxypeptidases as the Novel Biomarker in Pancreatic Ductal Adenocarcinoma

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Label-Free Quantitative Proteomics Unravels Carboxypeptidases as the Novel Biomarker in Pancreatic Ductal Adenocarcinoma