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Special Issue Editors

Special Issue Information

Dear Colleagues:

This Special Issue is a continuation of our 2018 Special Issue “Cell and Molecular Biology of Pancreatic Disorders”.

Pancreatic cancer is one of the deadliest cancers, with a 5 year survival rate of about 6%. Recent studies have elucidated the molecular mechanisms underlying the genesis and progression of this disease, which has enabled the development of novel therapeutics; while this is promising, however, it has not translated into prolonged survival rates due to the complex nature of the disease. Further, due to a lack of reliable early detection methods, the cancer is detected only at a late stage, when it is aggressive and highly invasive. Additionally, the highly fibrotic tumor microenvironment—which is enriched with growth factors and cytokines—significantly supports the growth and metastasis of the tumor and hinders the therapeutic efficacy. This thematic Special Issue is expected to cover the molecular and cellular mechanisms associated with pancreatic ductal adenocarcinomas, as well as the recent therapeutic strategies being developed to target specific signaling pathways. Other relevant aspects, such as the contribution of microenvironmental factors, cancer stem cells, behavior correlates such as smoking, and role of environmental pollutants in genesis and progression as well as response to therapy, will be covered in this issue. We expect that this Special Issue will provide the latest information on the mechanisms driving PDACs and will be of interest to scientists and clinicians working in this area.

Prof. Dr. Srikumar Chellappan
Dr. Jaya Padmanabhan
Guest Editors

Manuscript Submission Information

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Keywords

Signaling pathways in PDCACs
Novel therapeutic targets for PDACs
Pancreatic neuroendocrine tumors
Pancreatic intraepithelial neoplasia
Intraductal papillary mucinous neoplasms
Pancreatic cancer stem cells
Pancreatic stromal cells
Pancreatic microenvironment
Genetic changes
Transcription and translation
Cell metabolism
Intracellular and intercellular signaling
Genomics/proteomics/lipidomics
Inflammation
Metastasis

Published Papers (2 papers)

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Research

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25 pages, 7720 KiB

Open AccessArticle

Peptidylarginine Deiminase Inhibitor Application, Using Cl-Amidine, PAD2, PAD3 and PAD4 Isozyme-Specific Inhibitors in Pancreatic Cancer Cells, Reveals Roles for PAD2 and PAD3 in Cancer Invasion and Modulation of Extracellular Vesicle Signatures

by Pinar Uysal-Onganer, Stefania D’Alessio, Maria Mortoglou, Igor Kraev and Sigrun Lange

Int. J. Mol. Sci. 2021, 22(3), 1396; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031396 - 30 Jan 2021

Cited by 17 | Viewed by 4668

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with limited survival rate. Roles for peptidylarginine deiminases (PADs) have been studied in relation to a range of cancers with roles in epigenetic regulation (including histone modification and microRNA regulation), cancer invasion, and extracellular vesicle (EV) release. Hitherto though, knowledge on PADs in PDAC is limited. In the current study, two PDAC cell lines (Panc-1 and MiaPaCa-2) were treated with pan-PAD inhibitor Cl-amidine as well as PAD2, PAD3, and PAD4 isozyme-specific inhibitors. Effects were assessed on changes in EV signatures, including EV microRNA cargo (miR-21, miR-126, and miR-221), on changes in cellular protein expression relevant for pancreatic cancer progression and invasion (moesin), for mitochondrial housekeeping (prohibitin, PHB), and gene regulation (deiminated histone H3, citH3). The two pancreatic cancer cell lines were found to predominantly express PAD2 and PAD3, which were furthermore expressed at higher levels in Panc-1, compared with MiaPaCa-2 cells. PAD2 isozyme-specific inhibitor had the strongest effects on reducing Panc-1 cell invasion capability, which was accompanied by an increase in moesin expression, which in pancreatic cancer is found to be reduced and associated with pancreatic cancer aggressiveness. Some reduction, but not significant, was also found on PHB levels while effects on histone H3 deimination were variable. EV signatures were modulated in response to PAD inhibitor treatment, with the strongest effects observed for PAD2 inhibitor, followed by PAD3 inhibitor, showing significant reduction in pro-oncogenic EV microRNA cargo (miR-21, miR-221) and increase in anti-oncogenic microRNA cargo (miR-126). While PAD2 inhibitor, followed by PAD3 inhibitor, had most effects on reducing cancer cell invasion, elevating moesin expression, and modulating EV signatures, PAD4 inhibitor had negligible effects and pan-PAD inhibitor Cl-amidine was also less effective. Compared with MiaPaCa-2 cells, stronger modulatory effects for the PAD inhibitors were observed in Panc-1 cells, which importantly also showed strong response to PAD3 inhibitor, correlating with previous observations that Panc-1 cells display neuronal/stem-like properties. Our findings report novel PAD isozyme regulatory roles in PDAC, highlighting roles for PAD isozyme-specific treatment, depending on cancer type and cancer subtypes, including in PDAC. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research: Underlying Mechanisms and Therapeutic Targets)

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Review

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20 pages, 1561 KiB

Open AccessReview

Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting

by Utpreksha Vaish, Tejeshwar Jain, Abhi C. Are and Vikas Dudeja

Int. J. Mol. Sci. 2021, 22(24), 13408; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413408 - 14 Dec 2021

Cited by 43 | Viewed by 8294

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research: Underlying Mechanisms and Therapeutic Targets)

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