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Molecular Research on Pancreatic Cancer: From Pathology to Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 12761

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Special Issue Editor

Dr. Bo Kong

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Guest Editor

Department of Surgery, Ulm University Hospital, Ulm University, 89081 Ulm, Germany
Interests: early carcinogenesis; extracellular matrix; cancer-associated fibroblasts; immunotherapy; molecular subtypes

Special Issue Information

Dear Colleagues,

Despite enormous advances in molecular tumor biology, the overall survival rate of pancreatic ductal adenocarcinoma (PDAC) patients has remained unchanged for the past 20 years. This may be partially attributed to the fact that PDAC is a histopathologically defined tumor entity with extreme heterogeneity, on clinical, histological, and genetic levels. A variety of molecular subtypes with distinctive tumor biologies exist, but current therapies are applied without considering these putative differences. Abundant desmoplastic stroma is the prominent feature of PDAC, which mainly consists of cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), and immune cells. With advanced bioinformatic tools, single-cell and spatial transcriptome analysis on a transcriptional scale have enabled us to analyze cellular heterogeneity and subpopulations within cancer and the stroma compartments. As such, several subtypes of CAFs with distinctive characteristics have been identified. However, this novel knowledge is not yet translated into new therapies for PDAC patients.

In this Special Issue of IJMS, the focus will be on the impact of molecular pathology on patient outcomes by considering the biology of PDAC and new treatment options.

Suitable topics include, but are not limited to:

Molecular subtypes;
Targeted therapy;
Anti-stroma therapy;
Immunotherapy;
Tumor microenvironment.

Dr. Bo Kong
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 cancer
genetics
epigenetics
transcriptional subtype
tumor microenvironment

Published Papers (6 papers)

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Research

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19 pages, 4053 KiB

Open AccessArticle

Differential Effects of Pancreatic Cancer-Derived Extracellular Vesicles Driving a Suppressive Environment

by Anurag Purushothaman, Jacqueline Oliva-Ramírez, Warapen Treekitkarnmongkol, Deivendran Sankaran, Mark W. Hurd, Nagireddy Putluri, Anirban Maitra, Cara Haymaker and Subrata Sen

Int. J. Mol. Sci. 2023, 24(19), 14652; https://doi.org/10.3390/ijms241914652 - 27 Sep 2023

Cited by 1 | Viewed by 1320

Abstract

Pancreatic ductal adenocarcinoma (PDAC) cells display extensive crosstalk with their surrounding environment to regulate tumor growth, immune evasion, and metastasis. Recent advances have attributed many of these interactions to intercellular communication mediated by small extracellular vesicles (sEVs), involving cancer-associated fibroblasts (CAF). To explore the impact of sEVs on monocyte lineage transition as well as the expression of checkpoint receptors and activation markers, peripheral blood monocytes from healthy subjects were exposed to PDAC-derived sEVs. Additionally, to analyze the role of sEV-associated HA in immune regulation and tissue-resident fibroblasts, monocytes and pancreatic stellate cells were cultured in the presence of PDAC sEVs with or depleted of HA. Exposure of monocytes to sEVs resulted in unique phenotypic changes in HLA-DR, PD-L1, CD86 and CD64 expression, and cytokine secretion that was HA-independent except for IL-1β and MIP1β. In contrast, monocyte suppression of autologous T cell proliferation was reduced following exposure to HA-low sEVs. In addition, exposure of stellate cells to sEVs upregulated the secretion of various cytokines, including MMP-9, while removal of HA from PDAC-derived sEVs attenuated the secretion of MMP-9, demonstrating the role of sEV-associated HA in regulating expression of this pro-tumorigenic cytokine from stellate cells. This observation lends credence to the findings from the TCGA database that PDAC patients with high levels of enzymes in the HA synthesis pathway had worse survival rates compared with patients having low expression of these enzymes. PDAC-derived sEVs have an immune modulatory role affecting the activation state of monocyte subtypes. However, sEV-associated HA does not affect monocyte phenotype but alters cytokine secretion and suppression of autologous T cell proliferation and induces secretion of pro-tumorigenic factors by pancreatic stellate cells (PSC), as has been seen following the conversion of PSCs to cancer-associated fibroblasts (CAFs). Interruption of the hexosamine biosynthetic pathway, activated in PDAC producing the key substrate (UDP-GlcNAc) for HA synthesis, thus, represents a potential clinical interception strategy for PDAC patients. Findings warrant further investigations of underlying mechanisms involving larger sample cohorts. Full article

(This article belongs to the Special Issue Molecular Research on Pancreatic Cancer: From Pathology to Therapy)

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15 pages, 9632 KiB

Open AccessArticle

Salivary Polyamines Help Detect High-Risk Patients with Pancreatic Cancer: A Prospective Validation Study

by Daisuke Nose, Masahiro Sugimoto, Tsuneo Muta and Shin-Ichiro Miura

Int. J. Mol. Sci. 2023, 24(3), 2998; https://doi.org/10.3390/ijms24032998 - 3 Feb 2023

Cited by 4 | Viewed by 2527

Abstract

Pancreatic cancer is one of the most malignant cancer types and has a poor prognosis. It is often diagnosed at an advanced stage because of the absence of typical symptoms. Therefore, it is necessary to establish a screening method for the early detection of pancreatic cancer in high-risk individuals. This is a prospective validation study conducted in a cohort of 1033 Japanese individuals (male, n = 467, age = 63.3 ± 11.5 years; female, n = 566, age = 64.2 ± 10.6 years) to evaluate the use of salivary polyamines for screening pancreatic diseases and cancers. Patients with pancreatic cancer were not included; however, other pancreatic diseases were treated as positive cases for accuracy verification. Of the 135 individuals with elevated salivary polyamine markers, 66 had pancreatic diseases, such as chronic pancreatitis and pancreatic cysts, and 1 had gallbladder cancer. These results suggest that the salivary polyamine panel is a useful noninvasive pancreatic disease screening tool. Full article

(This article belongs to the Special Issue Molecular Research on Pancreatic Cancer: From Pathology to Therapy)

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Graphical abstract

13 pages, 2107 KiB

Open AccessArticle

The Immune Checkpoint Landscape in Tumor Cells of Pancreatic Ductal Adenocarcinoma

by Florian N. Loch, Carsten Kamphues, Katharina Beyer, Christian Schineis, Wael Rayya, Johannes C. Lauscher, David Horst, Mihnea P. Dragomir and Simon Schallenberg

Int. J. Mol. Sci. 2023, 24(3), 2160; https://doi.org/10.3390/ijms24032160 - 21 Jan 2023

Cited by 4 | Viewed by 1897

Abstract

Immune checkpoint therapy (ICT) has shown promising potential in the treatment of multiple solid tumors. However, the role of ICT in pancreatic ductal adenocarcinoma (PDAC) remains limited. Patterns of immune checkpoints (ICs) in PDAC represent the basis for establishing a potent ICT. The aim of this study is to create a profile of IC expression and its prognostic relevance in cancer cells of PDAC. Therefore, tumor cells from peripheral and central tissue microarray (TMA) spots from histologically confirmed PDAC of 68 patients after tumor resection were investigated in terms of expressions of TIM3, IDO, B7H4, LAG3, VISTA, and PD-L1 using immunohistochemistry. The presence of the respective ICs was compared to overall survival (OS). The presence of VISTA and PD-L1 significantly correlates with shorter OS (median OS: 22 months vs. 7 months and 22 months vs. 11 months, respectively, p < 0.05). For the presence of TIM3, IDO, B7H4, and LAG3, no difference in OS was observed (p > 0.05). The analysis of OS of combined subgroups for VISTA and PD-L1 (VISTA and PD-L1 neg., VISTA pos. and PD-L1 neg., VISTA neg. and PD-L1 pos., and VISTA and PD-L1 pos.) yielded overall statistical significance difference (p = 0.02). These results suggest that the presence of VISTA and PD-L1 is of prognostic relevance and potentially qualifies them as targets for ICT. Full article

(This article belongs to the Special Issue Molecular Research on Pancreatic Cancer: From Pathology to Therapy)

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15 pages, 4137 KiB

Open AccessArticle

C/EBP-Family Redundancy Determines Patient Survival and Lymph Node Involvement in PDAC

by Leonie Hartl, Joris J. T. H. Roelofs, Frederike Dijk, Maarten F. Bijlsma, JanWillem Duitman and C. Arnold Spek

Int. J. Mol. Sci. 2023, 24(2), 1537; https://doi.org/10.3390/ijms24021537 - 12 Jan 2023

Cited by 2 | Viewed by 1346

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor clinical prognosis and unsatisfactory treatment options. We previously found that the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) is lowly expressed in PDAC compared to healthy pancreas duct cells, and that patient survival and lymph node involvement in PDAC is correlated with the expression of C/EBPδ in primary tumor cells. C/EBPδ shares a homologous DNA-binding sequence with other C/EBP-proteins, leading to the presumption that other C/EBP-family members might act redundantly and compensate for the loss of C/EBPδ. This implies that patient stratification could be improved when expression levels of multiple C/EBP-family members are considered simultaneously. In this study, we assessed whether the quantification of C/EBPβ or C/EBPγ in addition to that of C/EBPδ might improve the prediction of patient survival and lymph node involvement using a cohort of 68 resectable PDAC patients. Using Kaplan–Meier analyses of patient groups with different C/EBP-expression levels, we found that both C/EBPβ and C/EBPγ can partially compensate for low C/EBPδ and improve patient survival. Further, we uncovered C/EBPβ as a novel predictor of a decreased likelihood of lymph node involvement in PDAC, and found that C/EBPβ and C/EBPδ can compensate for the lack of each other in order to reduce the risk of lymph node involvement. C/EBPγ, on the other hand, appears to promote lymph node involvement in the absence of C/EBPδ. Altogether, our results show that the redundancy of C/EBP-family members might have a profound influence on clinical prognoses and that the expression of both C/EPBβ and C/EBPγ should be taken into account when dichotomizing patients according to C/EBPδ expression. Full article

(This article belongs to the Special Issue Molecular Research on Pancreatic Cancer: From Pathology to Therapy)

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16 pages, 6315 KiB

Open AccessArticle

Gemcitabine Resistance in Pancreatic Ductal Carcinoma Cell Lines Stems from Reprogramming of Energy Metabolism

by Rina Fujiwara-Tani, Takamitsu Sasaki, Tadataka Takagi, Shiori Mori, Shingo Kishi, Yukiko Nishiguchi, Hitoshi Ohmori, Kiyomu Fujii and Hiroki Kuniyasu

Int. J. Mol. Sci. 2022, 23(14), 7824; https://doi.org/10.3390/ijms23147824 - 15 Jul 2022

Cited by 9 | Viewed by 2016

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis because it is often detected at an advanced stage, and drug resistance interferes with treatment. However, the mechanism underlying drug resistance in PDAC remains unclear. Here, we investigated metabolic changes between a parental PDAC cell line and a gemcitabine (GEM)-resistant PDAC cell line. We established a GEM-resistant cell line, MIA-G, from MIA-PaCa-2 parental (MIA-P) cells using continuous therapeutic-dose GEM treatment. MIA-G cells were also more resistant to 5-fluorouracil in comparison to MIA-P cells. Metabolic flux analysis showed a higher oxygen consumption rate (OCR) in MIA-G cells than in MIA-P cells. Notably, OCR was suppressed by GEM treatment only in MIA-G cells. GEM treatment increased mitochondrial membrane potential and mitochondrial reactive oxygen species (ROS) in MIA-P cells, but not in MIA-G cells. Glutamine uptake and peroxidase levels were elevated in MIA-G cells. The antioxidants N-acetyl-L-cysteine and vitamin C increased the sensitivity to GEM in both cell lines. In MIA-G cells, the expression of the mitochondrial transcription factor A also decreased. Furthermore, rotenone reduced the sensitivity of MIA-P cells to GEM. These findings suggest that the suppression of oxidative phosphorylation contributes to GEM resistance by reducing ROS production. Our study provides a new approach for reducing GEM resistance in PDAC. Full article

(This article belongs to the Special Issue Molecular Research on Pancreatic Cancer: From Pathology to Therapy)

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Review

Jump to: Research

19 pages, 1190 KiB

Open AccessReview

Mesenchymal Stromal Cell-Based Targeted Therapy Pancreatic Cancer: Progress and Challenges

by Zhilong Ma, Jie Hua, Jiang Liu, Bo Zhang, Wei Wang, Xianjun Yu and Jin Xu

Int. J. Mol. Sci. 2023, 24(4), 3559; https://doi.org/10.3390/ijms24043559 - 10 Feb 2023

Cited by 5 | Viewed by 2985

Abstract

Pancreatic cancer is an aggressive malignancy with high mortality rates and poor prognoses. Despite rapid progress in the diagnosis and treatment of pancreatic cancer, the efficacy of current therapeutic strategies remains limited. Hence, better alternative therapeutic options for treating pancreatic cancer need to be urgently explored. Mesenchymal stromal cells (MSCs) have recently received much attention as a potential therapy for pancreatic cancer owing to their tumor-homing properties. However, the specific antitumor effect of MSCs is still controversial. To this end, we aimed to focus on the potential anti-cancer treatment prospects of the MSC-based approach and summarize current challenges in the clinical application of MSCs to treat pancreatic cancer. Full article

(This article belongs to the Special Issue Molecular Research on Pancreatic Cancer: From Pathology to Therapy)

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