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Advanced Research in Pancreatic Ductal Adenocarcinoma

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Causes, Screening and Diagnosis".

Deadline for manuscript submissions: 30 September 2024 | Viewed by 13430

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Special Issue Editors

Prof. Dr. Stephan Kersting

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Guest Editor

Department of General, Visceral, Thoracic and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany
Interests: pancreatic cancer; pancreatic islet physiology; surgery; oncology

Prof. Dr. Robert Grützmann

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Guest Editor

Department of Surgery, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
Interests: pancreatic cancer; surgery; oncology
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Tobias Keck

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Guest Editor

Department of General, Visceral, Thoracic, Vascular and Transplantation Surgery, University Medical Center Schleswig- Holstein, 23538 Lübeck, Germany
Interests: pancreatic cancer; surgery; oncology

Special Issue Information

Dear Colleagues,

Despite all our research efforts in recent decades, pancreatic ductal adenocarcinoma (PDAC) today still has a dismal prognosis, with a median survival time of only 10–12 months. Due to the broad heterogeneity of genetic mutations and dense stromal environment, PDAC belongs to one of the most chemoresistant cancers. Due to the rapid upregulation of compensatory pathways and the dense desmoplastic reaction, therapies targeting cancer-associated molecular pathways have not given satisfactory results so far. There is an unmet clinical need to improve our understanding of the mechanisms underlying the carcinogenesis, progression, metastasis, as well as poor therapeutic responses seen in patients, of PDAC in the hopes of developing new therapeutic strategies, increasing drug efficacy, extending patient survival, and improving quality of life.

For this Special Issue, we welcome original and review papers that deal with the challenges and recent advances in pancreatic ductal adenocarcinoma. We are especially looking for papers that provide insight into new and original research methodologies, basic and molecular insights, clinical and translational research, improved diagnostics and early detection strategies, and new treatment approaches or surgical techniques.

Prof. Dr. Stephan Kersting
Prof. Dr. Robert Grützmann
Prof. Dr. Tobias Keck
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

pancreatic ductal adenocarcinoma

Published Papers (9 papers)

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Research

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15 pages, 5141 KiB

Open AccessArticle

Identifying the Spatial Architecture That Restricts the Proximity of CD8⁺ T Cells to Tumor Cells in Pancreatic Ductal Adenocarcinoma

by Yihan Xia, Junrui Ma, Xiaobao Yang, Danping Liu, Yujie Zhu, Yanan Zhao, Xuefeng Fei, Dakang Xu and Jing Dai

Cancers 2024, 16(7), 1434; https://doi.org/10.3390/cancers16071434 - 07 Apr 2024

Viewed by 626

Abstract

The anti-tumor function of CD8⁺ T cells is dependent on their proximity to tumor cells. Current studies have focused on the infiltration level of CD8⁺ T cells in the tumor microenvironment, while further spatial information, such as spatial localization and inter-cellular communication, have not been defined. In this study, co-detection by indexing (CODEX) was designed to characterize PDAC tissue regions with seven protein markers in order to identify the spatial architecture that regulates CD8⁺ T cells in human pancreatic ductal adenocarcinoma (PDAC). The cellular neighborhood algorithm was used to identify a total of six conserved and distinct cellular neighborhoods. Among these, one unique spatial architecture of CD8⁺ T and CD4⁺ T cell-enriched neighborhoods enriched the majority of CD8⁺ T cells, but heralded a poor prognosis. The proximity analysis revealed that the CD8⁺ T cells in this spatial architecture were significantly closer to themselves and the CD4⁺ T cells than to the tumor cells. Collectively, we identified a unique spatial architecture that restricted the proximity of CD8⁺ T cells to tumor cells in the tumor microenvironment, indicating a novel immune evasion mechanism of pancreatic ductal adenocarcinoma in a topologically regulated manner and providing new insights into the biology of PDAC. Full article

(This article belongs to the Special Issue Advanced Research in Pancreatic Ductal Adenocarcinoma)

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9 pages, 868 KiB

Open AccessArticle

Alternative Polyadenylation Characterizes Epithelial and Fibroblast Phenotypic Heterogeneity in Pancreatic Ductal Adenocarcinoma

by Swati Venkat and Michael E. Feigin

Cancers 2024, 16(3), 640; https://doi.org/10.3390/cancers16030640 - 02 Feb 2024

Viewed by 735

Abstract

Human tumors are characterized by extensive intratumoral transcriptional variability within the cancer cell and stromal compartments. This variation drives phenotypic heterogeneity, producing cell states with differential pro- and anti-tumorigenic properties. While bulk RNA sequencing cannot achieve cell-type-specific transcriptional granularity, single-cell sequencing has permitted an unprecedented view of these cell states. Despite this knowledge, we lack an understanding of the mechanistic drivers of this transcriptional and phenotypic heterogeneity. 3′ untranslated region alternative polyadenylation (3′ UTR-APA) drives gene expression alterations through regulation of 3′ UTR length. These 3′ UTR alterations modulate mRNA stability, protein expression and protein localization, resulting in cellular phenotypes including differentiation, cell proliferation, and migration. Therefore, we sought to determine whether 3′ UTR-APA events could characterize phenotypic heterogeneity of tumor cell states. Here, we analyze the largest single-cell human pancreatic ductal adenocarcinoma (PDAC) dataset and resolve 3′ UTR-APA patterns across PDAC cell states. We find that increased proximal 3′ UTR-APA is associated with PDAC progression and characterizes a metastatic ductal epithelial subpopulation and an inflammatory fibroblast population. Furthermore, we find significant 3′ UTR shortening events in cell-state-specific marker genes associated with increased expression. Therefore, we propose that 3′ UTR-APA drives phenotypic heterogeneity in cancer. Full article

(This article belongs to the Special Issue Advanced Research in Pancreatic Ductal Adenocarcinoma)

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20 pages, 6311 KiB

Open AccessArticle

The Prognostic and Immune Significance of CILP2 in Pan-Cancer and Its Relationship with the Progression of Pancreatic Cancer

by Danxi Liu, Cong He, Zonglin Liu, Licheng Xu, Jiacheng Li, Zhongjie Zhao, Xuewei Hu, Hua Chen, Bei Sun and Yongwei Wang

Cancers 2023, 15(24), 5842; https://doi.org/10.3390/cancers15245842 - 14 Dec 2023

Viewed by 916

Abstract

Cartilage intermediate layer protein 2 (CILP2) facilitates interactions between matrix components in cartilage and has emerged as a potential prognostic biomarker for cancer. This study aimed to investigate the function and mechanisms of CILP2 in pan-cancer. We evaluated the pan-cancer expression, methylation, and mutation data of CILP2 for its clinical prognostic value. Additionally, we explored the immunological characteristics of CILP2 in pan-cancer and then focused specifically on pancreatic ductal adenocarcinoma (PAAD). The subtype analysis of PAAD identified subtype-specific expression and immunological characteristics. Finally, in vitro and in vivo experiments assessed the impact of CILP2 on pancreatic cancer progression. CILP2 exhibited high expression in most malignancies, with significant heterogeneity in epigenetic modifications across multiple cancer types. The abnormal methylation and copy number variations in CILP2 were correlated with poor prognoses. Upregulated CILP2 was associated with TGFB/TGFBR1 and more malignant subtypes. CILP2 exhibited a negative correlation with immune checkpoints in PAAD, suggesting potential for immunotherapy. CILP2 activated the AKT pathway, and it increased proliferation, invasion, migration, and epithelial–mesenchymal transition (EMT) in pancreatic cancer. We demonstrated that CILP2 significantly contributes to pancreatic cancer progression. It serves as a prognostic biomarker and a potential target for immunotherapy. Full article

(This article belongs to the Special Issue Advanced Research in Pancreatic Ductal Adenocarcinoma)

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20 pages, 5648 KiB

Open AccessArticle

Impact of CRISPR/Cas9-Mediated CD73 Knockout in Pancreatic Cancer

by Jinping Zhang, Shuman Zhang, Isabella Dörflein, Xiaofan Ren, Susanne Pfeffer, Nathalie Britzen-Laurent, Robert Grützmann, Xianglong Duan and Christian Pilarsky

Cancers 2023, 15(19), 4842; https://doi.org/10.3390/cancers15194842 - 03 Oct 2023

Viewed by 1529

Abstract

Pancreatic cancer is among the cancers with the highest mortality rates. Most of the patients are found to have advanced cancer, losing the chance of surgical treatment, and there is an urgent need to find new treatment methods. Targeted therapy for specific genes that play a key role in cancer is now an important means to improve the survival rate of patients. We determined that CD73 is highly expressed in pancreatic cancer by flow cytometry and qRT-PCR assays combined with bioinformatics techniques. Application of CRISPR/Cas9 technology to knockout CD73 in human and murine cell lines, respectively, revealed that CD73 inactivation inhibited cell growth and migration and induced G1 cell cycle arrest. We also found that CD73 deletion inhibited the ERK/STAT3 pathway and activated the E-cadherin pathway. In addition, a CRISPR/Cas9 protein kinase library screen was performed and identified Pbk, Fastk, Cdk19, Adck5, Trim28, and Pfkp as possible genes regulating CD73. Full article

(This article belongs to the Special Issue Advanced Research in Pancreatic Ductal Adenocarcinoma)

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16 pages, 6116 KiB

Open AccessArticle

PD-1⁺CD8⁺ T Cells Proximal to PD-L1⁺CD68⁺ Macrophages Are Associated with Poor Prognosis in Pancreatic Ductal Adenocarcinoma Patients

by Xiaobao Yang, Guanzheng Wang, Yue Song, Tongtao Zhuang, Yifei Li, Yujie Xie, Xuefeng Fei, Yanan Zhao, Dakang Xu and Yiqun Hu

Cancers 2023, 15(5), 1389; https://doi.org/10.3390/cancers15051389 - 22 Feb 2023

Cited by 2 | Viewed by 1834

Abstract

Immune complexity status in the TME has been linked to clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. TME assessments with current cell marker and cell density-based analyses do not identify the original phenotypes of single cells with multilineage selectivity, the functional status of the cells, or cellular spatial information in the tissues. Here, we describe a method that circumvents these problems. The combined strategy of multiplexed IHC with computational image cytometry and multiparameter cytometric quantification allows us to assess multiple lineage-selective and functional phenotypic biomarkers in the TME. Our study revealed that the percentage of CD8⁺ T lymphoid cells expressing the T cell exhaustion marker PD-1 and the high expression of the checkpoint PD-L1 in CD68⁺ cells are associated with a poor prognosis. The prognostic value of this combined approach is more significant than that of lymphoid and myeloid cell density analyses. In addition, a spatial analysis revealed a correlation between the abundance of PD-L1⁺CD68⁺ tumor-associated macrophages and PD-1⁺CD8⁺T cell infiltration, indicating pro-tumor immunity associated with a poor prognosis. These data highlight the implications of practical monitoring for understanding the complexity of immune cells in situ. Digital imaging and multiparameter cytometric processing of cell phenotypes in the TME and tissue architecture can reveal biomarkers and assessment parameters for patient stratification. Full article

(This article belongs to the Special Issue Advanced Research in Pancreatic Ductal Adenocarcinoma)

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26 pages, 43101 KiB

Open AccessArticle

S100A10 Promotes Pancreatic Ductal Adenocarcinoma Cells Proliferation, Migration and Adhesion through JNK/LAMB3-LAMC2 Axis

by Hai Lin, Pengfei Yang, Bixiang Li, Yue Chang, Yutong Chen, Yaning Li, Kecheng Liu, Xinyue Liang, Tianliang Chen, Yalan Dai, Wenzheng Pang and Linjuan Zeng

Cancers 2023, 15(1), 202; https://doi.org/10.3390/cancers15010202 - 29 Dec 2022

Cited by 5 | Viewed by 1970

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors, characterized by diagnosis at an advanced stage and a poor prognosis. As a member of the S100 protein family, S100A10 regulates multiple biological functions related to cancer progression and metastasis. However, the role of S100A10 in PDAC is still not completely elucidated. In this study, we reported that S100A10 was significantly up-regulated in PDAC tissue and associated with a poor prognosis by integrated bioinformatic analysis and human PDAC tissue samples. In vitro, down-regulation of S100A10 reduced the proliferation, migration, and adhesion of PDAC cell lines, whereas up-regulation of S100A10 showed the opposite effect. Furthermore, LAMB3 was proved to be activated by S100A10 using RNA-sequencing and western blotting. The effect of LAMB3 on the proliferation, migration, and adhesion of PDAC cells was similar to that of S100A10. Up-regulation or down-regulation of LAMB3 could reverse the corresponding effect of S100A10. Moreover, we validated S100A10 activates LAMB3 through the JNK pathway, and LAMB3 was further proved to interact with LAMC2. Mice-bearing orthotopic pancreatic tumors showed that S100A10 knocked-down PANC-1 cells had a smaller tumor size than the control group. In conclusion, S100A10 promotes PDAC cells proliferation, migration, and adhesion through JNK/LAMB3-LAMC2 axis. Full article

(This article belongs to the Special Issue Advanced Research in Pancreatic Ductal Adenocarcinoma)

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28 pages, 9134 KiB

Open AccessArticle

DNA Polymerase Theta Plays a Critical Role in Pancreatic Cancer Development and Metastasis

by Agnieszka Smolinska, Kerstin Singer, Janine Golchert, Urszula Smyczynska, Wojciech Fendler, Matthias Sendler, Jens van den Brandt, Stephan Singer, Georg Homuth, Markus M. Lerch and Patryk Moskwa

Cancers 2022, 14(17), 4077; https://doi.org/10.3390/cancers14174077 - 23 Aug 2022

Cited by 5 | Viewed by 2191

Abstract

Pancreatic ductal adenocarcinoma (PDAC), due to its genomic heterogeneity and lack of effective treatment, despite decades of intensive research, will become the second leading cause of cancer-related deaths by 2030. Step-wise acquisition of mutations, due to genomic instability, is considered to drive the development of PDAC; the KRAS mutation occurs in 95 to 100% of human PDAC, and is already detectable in early premalignant lesions designated as pancreatic intraepithelial neoplasia (PanIN). This mutation is possibly the key event leading to genomic instability and PDAC development. Our study aimed to investigate the role of the error-prone DNA double-strand breaks (DSBs) repair pathway, alt-EJ, in the presence of the KRAS G12D mutation in pancreatic cancer development. Our findings show that oncogenic KRAS contributes to increasing the expression of Polθ, Lig3, and Mre11, key components of alt-EJ in both mouse and human PDAC models. We further confirm increased catalytic activity of alt-EJ in a mouse and human model of PDAC bearing the KRAS G12D mutation. Subsequently, we focused on estimating the impact of alt-EJ inactivation by polymerase theta (Polθ) deletion on pancreatic cancer development, and survival in genetically engineered mouse models (GEMMs) and cancer patients. Here, we show that even though Polθ deficiency does not fully prevent the development of pancreatic cancer, it significantly delays the onset of PanIN formation, prolongs the overall survival of experimental mice, and correlates with the overall survival of pancreatic cancer patients in the TCGA database. Our study clearly demonstrates the role of alt-EJ in the development of PDAC, and alt-EJ may be an attractive therapeutic target for pancreatic cancer patients. Full article

(This article belongs to the Special Issue Advanced Research in Pancreatic Ductal Adenocarcinoma)

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15 pages, 4295 KiB

Open AccessArticle

Visceral Surgery Profoundly Affects the Cellular and Humoral Components of the Anti-Tumour Immune Response in a Murine Pancreatic Adenocarcinoma Model

by Friederike Loening, Annabel Kleinwort, Lars Ivo Partecke, Tobias Schulze and Pia Menges

Cancers 2022, 14(16), 3850; https://doi.org/10.3390/cancers14163850 - 09 Aug 2022

Cited by 1 | Viewed by 1145

Abstract

(1) Background: Surgery is the most important element of multimodal treatment concepts in oncological patients, especially in the early stages of pancreatic tumours. While the influence of primary tumour resection on the immune status was analysed in several studies, the impact of tumour-unrelated visceral surgery on the tumour-bearing organism and on the primary tumour itself is not yet fully understood. (2) Methods: We combined a murine model of orthotopically implanted adenocarcinoma of the pancreas with the model of surgically-induced immune dysfunction (SID). Mortality and general condition including body weight were observed over a period of 28 days. Tumour growth was analysed by MRI scans on days 8 and 27 following tumour implantation. On day 28, the immune cell populations in the blood and spleen as well as the serum cytokines were quantified. (3) Results: SID results in a significant deterioration of the general condition and a reduced increase in the body weight of tumour-bearing mice compared to the control groups, while mortality and tumour growth rate were not influenced. The numbers of spleen macrophages and neutrophils were increased in tumour-bearing animals following SID. Furthermore, both macrophage and neutrophil levels were increased in the peripheral blood. (4) Conclusions: The presented results might contribute to the basic understanding of the interaction of tumour and immune system and could contribute to new approaches to immunotherapeutic strategies. Full article

(This article belongs to the Special Issue Advanced Research in Pancreatic Ductal Adenocarcinoma)

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Other

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27 pages, 3081 KiB

Open AccessSystematic Review

Understanding the Genetic Landscape of Pancreatic Ductal Adenocarcinoma to Support Personalized Medicine: A Systematic Review

by Antonino Pantaleo, Giovanna Forte, Candida Fasano, Martina Lepore Signorile, Paola Sanese, Katia De Marco, Elisabetta Di Nicola, Marialaura Latrofa, Valentina Grossi, Vittoria Disciglio and Cristiano Simone

Cancers 2024, 16(1), 56; https://doi.org/10.3390/cancers16010056 - 21 Dec 2023

Viewed by 1057

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. While population-wide screening recommendations for PDAC in asymptomatic individuals are not achievable due to its relatively low incidence, pancreatic cancer surveillance programs are recommended for patients with germline causative variants in PDAC susceptibility genes or a strong family history. In this study, we sought to determine the prevalence and significance of germline alterations in major genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, TP53) involved in PDAC susceptibility. We performed a systematic review of PubMed publications reporting germline variants identified in these genes in PDAC patients. Overall, the retrieved articles included 1493 PDAC patients. A high proportion of these patients (n = 1225/1493, 82%) were found to harbor alterations in genes (ATM, BRCA1, BRCA2, PALB2) involved in the homologous recombination repair (HRR) pathway. Specifically, the remaining PDAC patients were reported to carry alterations in genes playing a role in other cancer pathways (CDKN2A, STK11, TP53; n = 181/1493, 12.1%) or in the mismatch repair (MMR) pathway (MLH1, MSH2, MSH6, PMS2; n = 87/1493, 5.8%). Our findings highlight the importance of germline genetic characterization in PDAC patients for better personalized targeted therapies, clinical management, and surveillance. Full article

(This article belongs to the Special Issue Advanced Research in Pancreatic Ductal Adenocarcinoma)

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