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World Journal of Gastroenterology Feb 2022Pancreatic cystic lesions (PCLs) are becoming more prevalent due to more frequent abdominal imaging and the increasing age of the general population. It has become... (Review)
Review
Pancreatic cystic lesions (PCLs) are becoming more prevalent due to more frequent abdominal imaging and the increasing age of the general population. It has become crucial to identify these PCLs and subsequently risk stratify them to guide management. Given the high morbidity associated with pancreatic surgery, only those PCLs at high risk for malignancy should undergo such treatment. However, current diagnostic testing is suboptimal at accurately diagnosing and risk stratifying PCLs. Therefore, research has focused on developing new techniques for differentiating mucinous from non-mucinous PCLs and identifying high risk lesions for malignancy. Cross sectional imaging radiomics can potentially improve the predictive accuracy of primary risk stratification of PCLs at the time of detection to guide invasive testing. While cyst fluid glucose has reemerged as a potential biomarker, cyst fluid molecular markers have improved accuracy for identifying specific types of PCLs. Endoscopic ultrasound guided approaches such as confocal laser endomicroscopy and through the needle microforceps biopsy have shown a good correlation with histopathological findings and are evolving techniques for identifying and risk stratifying PCLs. While most of these recent diagnostics are only practiced at selective tertiary care centers, they hold a promise that management of PCLs will only get better in the future.
Topics: Cyst Fluid; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Humans; Pancreas; Pancreatic Cyst; Pancreatic Neoplasms
PubMed: 35317424
DOI: 10.3748/wjg.v28.i6.624 -
Journal of Experimental & Clinical... Oct 2022Cancer-associated fibroblasts (CAFs) are considered to play a fundamental role in pancreatic ductal adenocarcinoma (PDAC) progression and chemoresistance....
BACKGROUND
Cancer-associated fibroblasts (CAFs) are considered to play a fundamental role in pancreatic ductal adenocarcinoma (PDAC) progression and chemoresistance. Patient-derived organoids have demonstrated great potential as tumor avatars for drug response prediction in PDAC, yet they disregard the influence of stromal components on chemosensitivity.
METHODS
We established direct three-dimensional (3D) co-cultures of primary PDAC organoids and patient-matched CAFs to investigate the effect of the fibroblastic compartment on sensitivity to gemcitabine, 5-fluorouracil and paclitaxel treatments using an image-based drug assay. Single-cell RNA sequencing was performed for three organoid/CAF pairs in mono- and co-culture to uncover transcriptional changes induced by tumor-stroma interaction.
RESULTS
Upon co-culture with CAFs, we observed increased proliferation and reduced chemotherapy-induced cell death of PDAC organoids. Single-cell RNA sequencing data evidenced induction of a pro-inflammatory phenotype in CAFs in co-cultures. Organoids showed increased expression of genes associated with epithelial-to-mesenchymal transition (EMT) in co-cultures and several potential receptor-ligand interactions related to EMT were identified, supporting a key role of CAF-driven induction of EMT in PDAC chemoresistance.
CONCLUSIONS
Our results demonstrate the potential of personalized PDAC co-cultures models not only for drug response profiling but also for unraveling the molecular mechanisms involved in the chemoresistance-supporting role of the tumor stroma.
Topics: Humans; Coculture Techniques; Organoids; Drug Resistance, Neoplasm; Patient-Specific Modeling; Ligands; Stromal Cells; Cell Line, Tumor; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Cancer-Associated Fibroblasts; Paclitaxel; Fluorouracil; Antineoplastic Agents
PubMed: 36273171
DOI: 10.1186/s13046-022-02519-7 -
International Journal of Biological... 2021Pancreatic adenosquamous carcinoma (PASC) - a rare pathological pancreatic cancer (PC) type - has a poor prognosis due to high malignancy. To examine the heterogeneity...
Pancreatic adenosquamous carcinoma (PASC) - a rare pathological pancreatic cancer (PC) type - has a poor prognosis due to high malignancy. To examine the heterogeneity of PASC, we performed single-cell RNA sequencing (scRNA-seq) profiling with sample tissues from a healthy donor pancreas, an intraductal papillary mucinous neoplasm, and a patient with PASC. Of 9,887 individual cells, ten cell subpopulations were identified, including myeloid, immune, ductal, fibroblast, acinar, stellate, endothelial, and cancer cells. Cancer cells were divided into five clusters. Notably, cluster 1 exhibited stem-like phenotypes expressing UBE2C, ASPM, and TOP2A. We found that S100A2 is a potential biomarker for cancer cells. LGALS1, NPM1, RACK1, and PERP were upregulated from ductal to cancer cells. Furthermore, the copy number variations in ductal and cancer cells were greater than in the reference cells. The expression of EREG, FCGR2A, CCL4L2, and CTSC increased in myeloid cells from the normal pancreas to PASC. The gene sets expressed by cancer-associated fibroblasts were enriched in the immunosuppressive pathways. We demonstrate that EGFR-associated ligand-receptor pairs are activated in ductal-stromal cell communications. Hence, this study revealed the heterogeneous variations of ductal and stromal cells, defined cancer-associated signaling pathways, and deciphered intercellular interactions following PASC progression.
Topics: Adenocarcinoma, Mucinous; Biomarkers, Tumor; Carcinoma, Adenosquamous; Chemotactic Factors; DNA Copy Number Variations; ErbB Receptors; Genetic Heterogeneity; Humans; Neoplasm Proteins; Pancreatic Neoplasms; S100 Proteins; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome
PubMed: 34326696
DOI: 10.7150/ijbs.58886 -
Journal of B.U.ON. : Official Journal... 2020Insulinoma is the most common pancreatic neuroendocrine tumor (NET). Insulinomas are most commonly benign, well-differentiated NETs, whereas malignant neoplasms account... (Review)
Review
Insulinoma is the most common pancreatic neuroendocrine tumor (NET). Insulinomas are most commonly benign, well-differentiated NETs, whereas malignant neoplasms account for approximately 5-10% of all cases. Management includes conservative treatment with drugs targeting insulin-induced hypoglycemia, non-operative invasive procedures, as well as curative open or laparoscopic tumor resection. The current review aimed to summarize the current literature evidence on insulinoma and investigate the advantages and complications of available treatments.
Topics: Humans; Insulinoma; Laparoscopy; Pancreatic Neoplasms
PubMed: 32862570
DOI: No ID Found -
Surgery Today Jan 2020The current treatment strategy for intraductal papillary mucinous neoplasms (IPMNs), based on the international consensus guideline, has been accepted widely. However,... (Review)
Review
The current treatment strategy for intraductal papillary mucinous neoplasms (IPMNs), based on the international consensus guideline, has been accepted widely. However, reported outcomes after surgical resection for IPMN show that once the tumor progresses to invasive intraductal papillary mucinous carcinoma (IPMC), recurrence is not uncommon. The surgical treatment for IPMN is invasive and sometimes followed by complications. Therefore, the best timing for resection might be at the point when high-grade dysplasia (HGD) is evident. According to previous reports, main duct type IPMN has a high malignant potential and its surgical resection is universally accepted, whereas, the incidence of HGD/invasive IPMC in branch duct and mixed type IPMNs is thought to be lower. In addition to mural nodules and a dilated main pancreatic duct, cytology and measurement of the carcinoembryonic antigen level in the pancreatic juice might be useful to differentiate HGD/invasive IPMC from low-grade dysplasia. The nomogram proposed recently to predict the risk of HGD/invasive IPMC in IPMN patients might help surgeons decide on the best treatment strategy, depending on the patient's age and general condition. Second resection for high-risk lesions in the remnant pancreas might improve the survival of IPMN patients.
Topics: Age Factors; Biomarkers, Tumor; Carcinoembryonic Antigen; Humans; Lymph Node Excision; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Pancreas; Pancreatectomy; Pancreatic Intraductal Neoplasms; Pancreatic Juice; Pancreatic Neoplasms; Reoperation; Risk; Survival Rate; Treatment Outcome
PubMed: 31807871
DOI: 10.1007/s00595-019-01931-5 -
Gastroenterology Jan 2023Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been...
Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations That Improve the Clinical Management of Pancreatic Cysts.
BACKGROUND & AIMS
Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time.
METHODS
The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens.
RESULTS
Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations.
CONCLUSIONS
PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.
Topics: Humans; Retrospective Studies; Cystadenoma, Serous; Prospective Studies; Pancreatic Neoplasms; Pancreatic Cyst; High-Throughput Nucleotide Sequencing; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Genomics; Mitogen-Activated Protein Kinases
PubMed: 36209796
DOI: 10.1053/j.gastro.2022.09.028 -
Ugeskrift For Laeger Jun 2023Pancreatic cancer poses a challenge in healthcare and is one of a leading cause of cancer-related mortality. In 2021, around 1,000 new cases were diagnosed in Denmark.... (Review)
Review
Pancreatic cancer poses a challenge in healthcare and is one of a leading cause of cancer-related mortality. In 2021, around 1,000 new cases were diagnosed in Denmark. The disease itself is associated with a poor prognosis. Partly due to its silent nature and partly due to the lack of sensitive and specific tumour markers for early detection. The five-year survival rate among patients with pancreatic cancer in Denmark is 5-6%. I this review, we describe the current diagnostic and treatment options as well as the status on cancer-predictive biomarkers and their screening potential.
Topics: Humans; Early Detection of Cancer; Pancreatic Neoplasms; Biomarkers, Tumor; Prognosis
PubMed: 37325980
DOI: No ID Found -
Cancer Letters Dec 2023Tumor-associated macrophages (TAMs), as a major and essential component of tumor microenvironment (TME), play a critical role in orchestrating pancreatic cancer (PaC)...
Tumor-associated macrophages (TAMs), as a major and essential component of tumor microenvironment (TME), play a critical role in orchestrating pancreatic cancer (PaC) tumorigenesis from initiation to angiogenesis, growth, and systemic dissemination, as well as immunosuppression and resistance to chemotherapy and immunotherapy; however, the critical intrinsic factors responsible for TAMs reprograming and function remain to be identified. By performing single-cell RNA sequencing, transforming growth factor-beta-induced protein (TGFBI) was identified as TAM-producing factor in murine PaC tumors. TAMs express TGFBI in human PaC and TGFBI expression is positively related with human PaC growth. By inducing TGFBI loss-of-function in macrophage (MΦs) in vitro with siRNA and in vivo with Cre-Lox strategy in our developed TGFBI-floxed mice, we demonstrated disruption of TGFBI not only inhibited MΦ polarization to M2 phenotype and MΦ-mediated stimulation on PaC growth, but also significantly improved anti-tumor immunity, sensitizing PaC to chemotherapy in association with regulation of fibronectin 1, Cxcl10, and Ccl5. Our studies suggest that targeting TGFBI in MΦ can develop an effective therapeutic intervention for highly lethal PaC.
Topics: Animals; Humans; Mice; Drug Resistance, Neoplasm; Macrophages; Pancreatic Neoplasms; Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 37865162
DOI: 10.1016/j.canlet.2023.216457 -
Gastroenterology Mar 2021Pancreatic ductal adenocarcinomas (PDACs) are characterized by fibrosis and an abundance of cancer-associated fibroblasts (CAFs). We investigated strategies to disrupt... (Observational Study)
Observational Study
BACKGROUND & AIMS
Pancreatic ductal adenocarcinomas (PDACs) are characterized by fibrosis and an abundance of cancer-associated fibroblasts (CAFs). We investigated strategies to disrupt interactions among CAFs, the immune system, and cancer cells, focusing on adhesion molecule CDH11, which has been associated with other fibrotic disorders and is expressed by activated fibroblasts.
METHODS
We compared levels of CDH11 messenger RNA in human pancreatitis and pancreatic cancer tissues and cells with normal pancreas, and measured levels of CDH11 protein in human and mouse pancreatic lesions and normal tissues. We crossed p48-Cre;LSL-Kras;LSL-Trp53 (KPC) mice with CDH11-knockout mice and measured survival times of offspring. Pancreata were collected and analyzed by histology, immunohistochemistry, and (single-cell) RNA sequencing; RNA and proteins were identified by imaging mass cytometry. Some mice were given injections of PD1 antibody or gemcitabine and survival was monitored. Pancreatic cancer cells from KPC mice were subcutaneously injected into Cdh11 and Cdh11 mice and tumor growth was monitored. Pancreatic cancer cells (mT3) from KPC mice (C57BL/6), were subcutaneously injected into Cdh11 (C57BL/6J) mice and mice were given injections of antibody against CDH11, gemcitabine, or small molecule inhibitor of CDH11 (SD133) and tumor growth was monitored.
RESULTS
Levels of CDH11 messenger RNA and protein were significantly higher in CAFs than in pancreatic cancer epithelial cells, human or mouse pancreatic cancer cell lines, or immune cells. KPC/Cdh11 and KPC/Cdh11 mice survived significantly longer than KPC/Cdh11 mice. Markers of stromal activation entirely surrounded pancreatic intraepithelial neoplasias in KPC/Cdh11 mice and incompletely in KPC/Cdh11 and KPC/Cdh11 mice, whose lesions also contained fewer FOXP3 cells in the tumor center. Compared with pancreatic tumors in KPC/Cdh11 mice, tumors of KPC/Cdh11 mice had increased markers of antigen processing and presentation; more lymphocytes and associated cytokines; decreased extracellular matrix components; and reductions in markers and cytokines associated with immunosuppression. Administration of the PD1 antibody did not prolong survival of KPC mice with 0, 1, or 2 alleles of Cdh11. Gemcitabine extended survival of KPC/Cdh11 and KPC/Cdh11 mice only or reduced subcutaneous tumor growth in mT3 engrafted Cdh11 mice when given in combination with the CDH11 antibody. A small molecule inhibitor of CDH11 reduced growth of pre-established mT3 subcutaneous tumors only if T and B cells were present in mice.
CONCLUSIONS
Knockout or inhibition of CDH11, which is expressed by CAFs in the pancreatic tumor stroma, reduces growth of pancreatic tumors, increases their response to gemcitabine, and significantly extends survival of mice. CDH11 promotes immunosuppression and extracellular matrix deposition, and might be developed as a therapeutic target for pancreatic cancer.
Topics: Animals; Cadherins; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Deoxycytidine; Disease Models, Animal; Disease Progression; Drug Resistance, Neoplasm; Extracellular Matrix; Female; Gene Expression Regulation, Neoplastic; Humans; Metallothionein 3; Mice; Mice, Knockout; Pancreas; Pancreatic Neoplasms; Pancreaticoduodenectomy; Tumor Escape; Tumor Microenvironment; Gemcitabine
PubMed: 33307028
DOI: 10.1053/j.gastro.2020.11.044 -
The Journal of Experimental Medicine Aug 2020CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by...
CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated by CD8+ T cells infiltrating both murine and human tumors. In this lipid-rich but otherwise nutrient-poor TME, access to using lipid metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic CD8+ T cells progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair their mitochondrial function and trigger major transcriptional reprogramming of pathways involved in lipid metabolism, with the subsequent reduction of fatty acid catabolism. In particular, intrapancreatic CD8+ T cells specifically exhibit down-regulation of the very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates accumulation of LCFAs and very-long-chain fatty acids (VLCFAs) that mediate lipotoxicity. Metabolic reprogramming of tumor-specific T cells through enforced expression of ACADVL enabled enhanced intratumoral T cell survival and persistence in an engineered mouse model of PDA, overcoming one of the major hurdles to immunotherapy for PDA.
Topics: Acyl-CoA Dehydrogenase, Long-Chain; Animals; CD8-Positive T-Lymphocytes; Carcinoma, Pancreatic Ductal; Down-Regulation; Fatty Acids; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Mutant Strains; Neoplasm Proteins; Pancreas; Pancreatic Neoplasms; Tumor Microenvironment
PubMed: 32491160
DOI: 10.1084/jem.20191920