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Nature Communications Mar 2024The existing Intraductal Papillary Mucinous Neoplasm (IPMN) risk stratification relies on clinical and histological factors, resulting in inaccuracies and leading to...
The existing Intraductal Papillary Mucinous Neoplasm (IPMN) risk stratification relies on clinical and histological factors, resulting in inaccuracies and leading to suboptimal treatment. This is due to the lack of appropriate molecular markers that can guide patients toward the best therapeutic options. Here, we assess and confirm subtype-specific markers for IPMN across two independent cohorts of patients using two Spatial Transcriptomics (ST) technologies. Specifically, we identify HOXB3 and ZNF117 as markers for Low-Grade Dysplasia, SPDEF and gastric neck cell markers in borderline cases, and NKX6-2 and gastric isthmus cell markers in High-Grade-Dysplasia Gastric IPMN, highlighting the role of TNFα and MYC activation in IPMN progression and the role of NKX6-2 in the specific Gastric IPMN progression. In conclusion, our work provides a step forward in understanding the gene expression landscapes of IPMN and the critical transcriptional networks related to PDAC progression.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Intraductal Neoplasms; Adenocarcinoma, Mucinous; Pancreatic Neoplasms; Hyperplasia; Homeodomain Proteins
PubMed: 38553466
DOI: 10.1038/s41467-024-46994-2 -
Advanced Science (Weinheim,... Apr 2024One major obstacle in the drug treatment of pancreatic ductal adenocarcinoma (PDAC) is its highly fibrotic tumor microenvironment, which is replete with activated...
One major obstacle in the drug treatment of pancreatic ductal adenocarcinoma (PDAC) is its highly fibrotic tumor microenvironment, which is replete with activated pancreatic stellate cells (a-PSCs). These a-PSCs generate abundant extracellular matrix and secrete various cytokines to form biophysical and biochemical barriers, impeding drug access to tumor tissues. Therefore, it is imperative to develop a strategy for reversing PSC activation and thereby removing the barriers to facilitate PDAC drug treatment. Herein, by integrating chromatin immunoprecipitation (ChIP)-seq, Assays for Transposase-Accessible Chromatin (ATAC)-seq, and RNA-seq techniques, this work reveals that super-enhancers (SEs) promote the expression of various genes involved in PSC activation. Disruption of SE-associated transcription with JQ1 reverses the activated phenotype of a-PSCs and decreases stromal fibrosis in both orthotopic and patient-derived xenograft (PDX) models. More importantly, disruption of SEs by JQ1 treatments promotes vascularization, facilitates drug delivery, and alters the immune landscape in PDAC, thereby improving the efficacies of both chemotherapy (with gemcitabine) and immunotherapy (with IL-12). In summary, this study not only elucidates the contribution of SEs of a-PSCs in shaping the PDAC tumor microenvironment but also highlights that targeting SEs in a-PSCs may become a gate-opening strategy that benefits PDAC drug therapy by removing stromal barriers.
Topics: Pancreatic Stellate Cells; Pancreatic Neoplasms; Humans; Animals; Mice; Immunotherapy; Tumor Microenvironment; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Gemcitabine; Deoxycytidine; Azepines; Cell Line, Tumor; Triazoles
PubMed: 38417121
DOI: 10.1002/advs.202308637 -
Cell Reports May 2024Metastasis is one of the defining features of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor prognosis. In this study, the palmitoyl transferase...
Metastasis is one of the defining features of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor prognosis. In this study, the palmitoyl transferase ZDHHC20 was identified in an in vivo short hairpin RNA (shRNA) screen as critical for metastatic outgrowth, with no effect on proliferation and migration in vitro or primary PDAC growth in mice. This phenotype is abrogated in immunocompromised animals and animals with depleted natural killer (NK) cells, indicating that ZDHHC20 affects the interaction of tumor cells and the innate immune system. Using a chemical genetics platform for ZDHHC20-specific substrate profiling, a number of substrates of this enzyme were identified. These results describe a role for palmitoylation in enabling distant metastasis that could not have been detected using in vitro screening approaches and identify potential effectors through which ZDHHC20 promotes metastasis of PDAC.
Topics: Animals; Humans; Pancreatic Neoplasms; Acyltransferases; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Neoplasm Metastasis; Cell Proliferation; Cell Movement; Killer Cells, Natural; Lipoylation
PubMed: 38733589
DOI: 10.1016/j.celrep.2024.114224 -
Clinical Cancer Research : An Official... Oct 2023CA19-9 synthesis is influenced by common variants in the fucosyltransferase (FUT) enzymes FUT3 and FUT2. We developed a clinical test to detect FUT variants, and...
PURPOSE
CA19-9 synthesis is influenced by common variants in the fucosyltransferase (FUT) enzymes FUT3 and FUT2. We developed a clinical test to detect FUT variants, and evaluated its diagnostic performance for pancreatic ductal adenocarcinoma (PDAC).
EXPERIMENTAL DESIGN
A representative set of controls from the Cancer of the Pancreas Screening study was identified for each FUT functional group. Diagnostic sensitivity was determined first in a testing set of 234 PDAC cases, followed by a 134-case validation set, all of whom had undergone resection with curative intent without neoadjuvant therapy. Tumor marker gene testing was performed in the Johns Hopkins Molecular Diagnostics Laboratory. CA19-9 levels were measured in the Hopkins Clinical Chemistry lab. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative ability of CA19-9 alone versus with the gene test.
RESULTS
Applying the CA19-9 standard cutoff (<36 U/mL) to all 716 subjects yielded a 68.8% sensitivity in the test set of cases, 67.2% in the validation set, at 91.4% specificity. Applying 99th percentile cutoffs according to each individual's FUT group (3, 34.9, 41.8, and 89.2, for the FUT3-null, FUT-low, FUT-intermediate, and FUT-high groups, respectively) yielded a diagnostic sensitivity for CA19-9 in the first set of cases of 66.7%, 65.7% in the validation set, at 98.9% specificity. ROC analysis for CA19-9 alone yielded an AUC of 0.84; with the tumor marker gene test, AUC improved to 0.92 (P < 0.001).
CONCLUSIONS
Using a tumor marker gene test to personalize an individual's CA19-9 reference range significantly improves diagnostic accuracy.
Topics: Humans; CA-19-9 Antigen; Reference Values; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Biomarkers, Tumor; ROC Curve
PubMed: 37566230
DOI: 10.1158/1078-0432.CCR-23-0655 -
Frontiers in Immunology 2024One of the most deadly and aggressive cancers in the world, pancreatic ductal adenocarcinoma (PDAC), typically manifests at an advanced stage. PDAC is becoming more... (Review)
Review
One of the most deadly and aggressive cancers in the world, pancreatic ductal adenocarcinoma (PDAC), typically manifests at an advanced stage. PDAC is becoming more common, and by the year 2030, it is expected to overtake lung cancer as the second greatest cause of cancer-related death. The poor prognosis can be attributed to a number of factors, including difficulties in early identification, a poor probability of curative radical resection, limited response to chemotherapy and radiotherapy, and its immunotherapy resistance. Furthermore, an extensive desmoplastic stroma that surrounds PDAC forms a mechanical barrier that prevents vascularization and promotes poor immune cell penetration. Phenotypic heterogeneity, drug resistance, and immunosuppressive tumor microenvironment are the main causes of PDAC aggressiveness. There is a complex and dynamic interaction between tumor cells in PDAC with stromal cells within the tumour immune microenvironment. The immune suppressive microenvironment that promotes PDAC aggressiveness is contributed by a range of cellular and humoral factors, which itself are modulated by the cancer. In this review, we describe the role of innate and adaptive immune cells, complex tumor microenvironment in PDAC, humoral factors, innate immune-mediated therapeutic advances, and recent clinical trials in PDAC.
Topics: Humans; Tumor Microenvironment; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Immunotherapy
PubMed: 38384463
DOI: 10.3389/fimmu.2024.1323198 -
Annals of African Medicine 2023Resection of pancreatic tissue is necessary for many pancreatic diseases. The most common form of cancer, pancreatic duct adenocarcinoma, manifests with early metastases...
INTRODUCTION
Resection of pancreatic tissue is necessary for many pancreatic diseases. The most common form of cancer, pancreatic duct adenocarcinoma, manifests with early metastases and is thought to be resistant to other currently known treatment regimens. Such tumors present a complex and difficult management and handling challenge for a surgeon. Surgical resection affords a better prognosis with a median survival of 14-20 months following resection and up to 25% 5-year survival rates. In this study, data from 75 pancreatic resections for diverse malignant pancreatic lesions will be presented.
METHODS
At a teaching institute in Central India, this ongoing longitudinal study began in 2009 and was carried on till 2018. Only 75 of the 122 patients who underwent pancreatic resection were deemed appropriate for the current study. All patients were thoroughly examined after being admitted before being given the option of surgery. There were 22 female patients and 53 male patients. The age range for the group was 34-67 years. Results from a range of different malignancies and various pancreatic resection procedures are presented in this study.
RESULTS
One of the most aggressive cancers, pancreatic adenocarcinoma, responds to surgical treatment better than other alternative techniques. Out of 75 patients in our series, 32 had pancreatic head cancer, 28 had periampullary cancer, 2 had duodenal cancer, 8 had distal cholangiocarcinoma, and 1 had mucin-producing cystadenocarcinoma. Four patients had pancreatic cancer in both the body and tail. Fifty-three men and 22 women, ages 34-67 years, Whipple's operation and distal pancreatectomy were the most frequent procedures. In our series, survival ranged from 18 to 24 months, and the 5-year survival rate was 12%, which is primarily seen with periampullary carcinoma.
CONCLUSION
The sole option for long-term survival or a cure for pancreatic cancer is surgery. Chemoradiation is ineffective as a first line of treatment. However, some reports contend that palliative chemotherapy actually improves the quality of life. The biology of the illness rules and determines the result; the kind of surgery performed had no bearing on survival, morbidity, or fatality.
CONTEXT
The above study was taken up in the context of - pancreatic tumors and pathological types, how imaging helps in deciding the plan of surgical management without biopsy. Outcomes of pancreatic resections for pancreatic cancer.
SETTINGS AND DESIGN
In a suburban hospital which is a tertiary care center, this longitudinal prospective study was conducted from 2009 to 2018.
Topics: Humans; Male; Female; Adult; Middle Aged; Aged; Pancreatectomy; Pancreatic Neoplasms; Adenocarcinoma; Longitudinal Studies; Prospective Studies; Quality of Life; Hospitals
PubMed: 38358158
DOI: 10.4103/aam.aam_165_22 -
Cancer Research Communications Sep 2023Cleavage of erythropoietin-producing hepatocellular ephrin receptor A2 (EphA2) triggers malignant progression and yields an N-terminal fragment (EphA2-NF) detectable in...
UNLABELLED
Cleavage of erythropoietin-producing hepatocellular ephrin receptor A2 (EphA2) triggers malignant progression and yields an N-terminal fragment (EphA2-NF) detectable in sera from patients with pancreatic ductal carcinoma. We established a quantitative automated chemiluminescence immunoassay for EphA2-NF and evaluated serum EphA2-NF levels as a biomarker to diagnose pancreatic ductal carcinoma in the test and validation cohorts. The EphA2-NF value was elevated (above the cutoff: mean ± SD) in more than half of the patients with stage I/II pancreatic ductal carcinoma. Among patients receiving standard chemotherapy for pancreatic ductal carcinoma [gemcitabine plus nab-paclitaxel (GnP)], the median survival time of patients with elevated serum EphA2-NF was half that of patients with values below the cutoff. Patients with intraductal papillary mucinous neoplasm (IPMN), a precancerous pancreatic ductal carcinoma lesion, also show high serum EphA2 levels, which are associated with an increase in pancreatic duct size and the development of pancreatic ductal carcinoma in some cases. IHC showed loss of EphA2-NF staining in IPMN with pancreatic ductal carcinoma, but not in the normal epithelium or IPMN without pancreatic ductal carcinoma, regardless of the histologic grade. These results suggest that EphA2 cleavage is an essential event that occurs very early in pancreatic ductal carcinoma development, and that the consequent release of EphA2-NF can be detected in the serum. Thus, serum EphA2-NF could be a diagnostic biomarker for very early-stage pancreatic ductal carcinoma and pancreatic ductal carcinoma development from high-risk IPMN and as a prognostic biomarker after chemotherapy with GnP.
SIGNIFICANCE
EphA2 N-terminus deletion is involved in pancreatic ductal carcinoma development from high-risk IPMN and EphA2-NF produced by cleavage can be used as a serum biomarker to diagnose pancreatic ductal carcinoma and predict pancreatic ductal carcinoma development from high-risk IPMN.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Intraductal Neoplasms; Peptide Hydrolases; Proteolysis; Pancreatic Neoplasms
PubMed: 37712876
DOI: 10.1158/2767-9764.CRC-23-0087 -
Seminars in Cancer Biology Nov 2023Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer alarmingly expanding in our modern societies that is still proving to be very challenging to counteract. This... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer alarmingly expanding in our modern societies that is still proving to be very challenging to counteract. This disease constitutes a quintessential example of the multiple interactions existing between the tumour and its surrounding microenvironment. In particular, PDAC is characterized by a very immunosuppressive environment that favours cancer growth and makes this cancer type very resistant to immunotherapy. The primary tumour releases many factors that influence both the microenvironment and the immune landscape. Extracellular vesicles (EVs), recently identified as indispensable entities ensuring cell-to-cell communication in both physiological and pathological processes, seem to play a pivotal function in ensuring the delivery of these factors to the tumour-surrounding tissues. In this review, we summarize the present understanding on the crosstalk among tumour cells and the cellular immune microenvironment emphasizing the pro-malignant role played by extracellular vesicles. We also discuss how a greater knowledge of the roles of EVs in tumour immune escape could be translated into clinical applications.
Topics: Humans; Immune Evasion; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Extracellular Vesicles; Tumor Microenvironment
PubMed: 37748738
DOI: 10.1016/j.semcancer.2023.09.004 -
Cell Death & Disease Nov 2023Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer most frequently detected at an advanced stage that limits treatment options to systemic...
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer most frequently detected at an advanced stage that limits treatment options to systemic chemotherapy, which has provided only marginal positive clinical outcomes. Currently, the first-line chemotherapeutic agent for PDAC is gemcitabine (GEM). However, the chemotherapy resistance to GEM is often overlooked in the clinical treatment of PDAC due to the lack of effective biological markers. Therefore, it is crucial to find new prognostic markers and therapeutic targets for patients with PDAC. In this study, we identified a novel regulatory mechanism in the development of resistance to GEM in PDAC. Here, we report that LINC01134 was significantly upregulated in primary tumors from PDAC patients. In vitro and in vivo functional studies revealed that LINC01134 promotes PDAC resistance to GEM through facilitating stem cell features and modulating the cell cycle. Mechanistically, LINC01134 interactes with tumor suppressor miR-497-5p in PDAC cells. Increased LINC01134 downregulates miR-140-3p to promotes the oncogenic WNT5A expression. Moreover, mA demethylase FTO participated in the upregulation of LINC01134 by maintaining LINC01134 mRNA stability through YTHDF2. Taken together, the present study suggested FTO-mediated LINC01134 stabilization to promote chemotherapy resistance to GEM through miR-140-3p/WNT5A/WNT pathway in PDAC. Our study identified new prognostic markers and new therapeutic targets for patients with PDAC.
Topics: Humans; Drug Resistance, Neoplasm; Deoxycytidine; Wnt Signaling Pathway; Carcinoma, Pancreatic Ductal; Gemcitabine; Pancreatic Neoplasms; MicroRNAs; Cell Line, Tumor; Wnt-5a Protein; Alpha-Ketoglutarate-Dependent Dioxygenase FTO
PubMed: 37914721
DOI: 10.1038/s41419-023-06244-7 -
Pancreatology : Official Journal of the... Dec 2023Probing relevant proteomic biomarkers may facilitate effective pancreatic adenocarcinoma (PDAC) diagnosis, treatment and prevention. Here, we developed a protein-based...
BACKGROUND
Probing relevant proteomic biomarkers may facilitate effective pancreatic adenocarcinoma (PDAC) diagnosis, treatment and prevention. Here, we developed a protein-based prognostic model for PDAC by using relevant proteomic biomarkers data from The Cancer Genome Atlas (TCGA).
METHODS
We obtained PDAC's proteomic and clinical data from TCGA and used various analytical tools to identify differentially expressed proteins between normal and cancer tissues. We constructed our protein-based prognostic model and confirmed its accuracy using receiver operating characteristic curve and Kaplan-Meier survival analyses. We elucidated clinical factor-signature protein correlations by clinical correlation assessments and protein coexpression networks. We also used immunohistochemistry (protein expression assessment), Gene Set Enrichment Analysis (protein role identification) and CIBERSORT (infiltrating immune cell distribution assessment).
RESULTS
CIITA, BRAF_pS445, AR, YTHDF2, IGFBP2 and CDK1_pT14 were identified as PDAC-associated prognostic proteins. All risk scores calculated using our model provided 1-, 3-, 5-year survival probability at 70 % accuracy. The reliability of our model was validated by the GEO as well. In high- and low-risk groups, age, sex, T- and N- stage disparities were significant, and prognostic and coexpressed proteins correlated. PDAC tissues demonstrated significant CDK1_pT14 overexpression but significant BRAF_pS445, YTHDF2, and IGFBP2 underexpression. Downstream proteins of BRAF were validated by IHC. Low-risk tissues demonstrated more naïve B cells, eosinophils, activated NK cells and regulatory T cells, whereas high-risk tissues demonstrated more activated memory T cells, monocytes, neutrophils, dendritic cells and resting NK cells.
CONCLUSIONS
Our protein-based prognostic model for PDAC, along with six signature proteins, might aid in predicting PDAC prognosis and therapeutic targets.
Topics: Humans; Pancreatic Neoplasms; Prognosis; Adenocarcinoma; Proteomics; Proto-Oncogene Proteins B-raf; Reproducibility of Results; Carcinoma, Pancreatic Ductal; Biomarkers; Biomarkers, Tumor
PubMed: 37923686
DOI: 10.1016/j.pan.2023.10.021