Special Issue "Epigenetics of Pancreatic Cancer"

A special issue of Epigenomes (ISSN 2075-4655).

Deadline for manuscript submissions: closed (15 May 2018)

Special Issue Editors

Guest Editor
Dr. Martin E. Fernandez-Zapico

Schulze Center for Novel Therapeutics, Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA
Website | E-Mail
Interests: pancreatic cancer, tumor microenvironment, histone methylation, nuclear and chromatin organization
Guest Editor
Dr. Christopher Pin

Division Head and Scientist, Genetics and Development, Children's Health Research Institute Associate Professor, Depts. of Paediatrics, Physiology and Pharmacology, and Oncology Schulich School of Medicine and Dentistry, University of Western Ontario
Website | E-Mail
Interests: epigenetic regulation of pancreatic development and disease; acinar-to-duct cell metaplasia; unfolded protein response; ER stress; acinar cell physiology

Special Issue Information

Dear Colleagues,

This Special Issue focuses on the role of epigenetics in pancreatic cancer, a dismal disease predicted to be second cause of cancer death by 2030. This aggressive and rapidly-disseminated epithelial neoplasm is highly resistant to conventional chemotherapeutic and radiation-based treatments. The past several decades of pancreatic cancer research have yielded a tremendous amount of knowledge about the genetics of tumor cells; however, this knowledge has not translated into significant clinical advances in treatment and prevention. These genetic-based drivers of pancreatic cancer have been well studied, but they do not account for all of the phenotypic and molecular alterations demonstrated by tumor cells. Pancreatic cancer initiation and progression is the result of a heterogeneous and dynamic combination of both genetic and epigenetic mechanisms. With the identification of epigenetic alterations seen in early pancreatic preneoplastic lesions through the development of pancreatic cancer, there implies an inherent complexity in epigenetic changes that occurs in parallel to genetic changes. This Special Issue will discuss on the present knowledge in field pancreatic cancer epigenetics and will be composed of the following works (see planned papers)

Dr. Martin E. Fernandez-Zapico
Dr. Christopher Pin
Guest Editors

Manuscript Submission Information

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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. Epigenomes is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) is waived for well-prepared manuscripts submitted to this issue. 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
  • epigenetics
  • chromatin dynamics
  • therapeutic
  • biomarkers

Published Papers (4 papers)

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Review

Open AccessReview Nuclear Envelope Regulation of Oncogenic Processes: Roles in Pancreatic Cancer
Received: 10 August 2018 / Revised: 30 August 2018 / Accepted: 31 August 2018 / Published: 2 September 2018
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Abstract
Pancreatic cancer is an aggressive and intractable malignancy with high mortality. This is due in part to a high resistance to chemotherapeutics and radiation treatment conferred by diverse regulatory mechanisms. Among these, constituents of the nuclear envelope play a significant role in regulating
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Pancreatic cancer is an aggressive and intractable malignancy with high mortality. This is due in part to a high resistance to chemotherapeutics and radiation treatment conferred by diverse regulatory mechanisms. Among these, constituents of the nuclear envelope play a significant role in regulating oncogenesis and pancreatic tumor biology, and this review focuses on three specific components and their roles in cancer. The LINC complex is a nuclear envelope component formed by proteins with SUN and KASH domains that interact in the periplasmic space of the nuclear envelope. These interactions functionally and structurally couple the cytoskeleton to chromatin and facilitates gene regulation informed by cytoplasmic activity. Furthermore, cancer cell invasiveness is impacted by LINC complex biology. The nuclear lamina is adjacent to the inner nuclear membrane of the nuclear envelope and can actively regulate chromatin in addition to providing structural integrity to the nucleus. A disrupted lamina can impart biophysical compromise to nuclear structure and function, as well as form dysfunctional micronuclei that may lead to genomic instability and chromothripsis. In close relationship to the nuclear lamina is the nuclear pore complex, a large megadalton structure that spans both outer and inner membranes of the nuclear envelope. The nuclear pore complex mediates bidirectional nucleocytoplasmic transport and is comprised of specialized proteins called nucleoporins that are overexpressed in many cancers and are diagnostic markers for oncogenesis. Furthermore, recent demonstration of gene regulatory functions for discrete nucleoporins independent of their nuclear trafficking function suggests that these proteins may contribute more to malignant phenotypes beyond serving as biomarkers. The nuclear envelope is thus a complex, intricate regulator of cell signaling, with roles in pancreatic tumorigenesis and general oncogenic transformation. Full article
(This article belongs to the Special Issue Epigenetics of Pancreatic Cancer)
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Open AccessReview Recent Advances in Chromatin Mechanisms Controlling Pancreatic Carcinogenesis
Received: 31 May 2018 / Revised: 14 June 2018 / Accepted: 15 June 2018 / Published: 20 June 2018
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Abstract
Pancreatic ductal adenocarcinoma has a heterogeneous genetic landscape, marked by frequent mutation of KRAS, CDKN2A, TP53, and SMAD4, resulting in poor responses to conventional therapeutic regimens. Over the past decade, increased understanding of the genetic underpinnings of this lethal
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Pancreatic ductal adenocarcinoma has a heterogeneous genetic landscape, marked by frequent mutation of KRAS, CDKN2A, TP53, and SMAD4, resulting in poor responses to conventional therapeutic regimens. Over the past decade, increased understanding of the genetic underpinnings of this lethal cancer has yielded several different characterizations of pancreatic cancer subtypes. However, not all phenotypes and changes in pancreatic cancer can be explained by these findings. New insights on epigenetic modifications associated with pancreatic carcinogenesis have highlighted additional pathways, other than gene mutations, among which chromatin regulation plays a dominant role. Gene expression is highly regulated by subtle changes in chromatin configuration. The underlying mechanism is dominated by reversible post-translational histone modifications. In addition, there is growing evidence that different chromatin mechanisms interact with one another, contributing to the diversity of pancreatic carcinogenesis. This review highlights recent work characterizing chromatin regulatory mechanisms associated with pancreatic carcinogenesis as well as future directions of this emerging research. Full article
(This article belongs to the Special Issue Epigenetics of Pancreatic Cancer)
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Open AccessReview The Epigenetic Landscape of Pancreatic Cancer Stem Cells
Received: 31 May 2018 / Revised: 8 June 2018 / Accepted: 11 June 2018 / Published: 14 June 2018
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Abstract
Data now indicates that in addition to genetic alterations/mutations, human cancer cells exhibit important changes in their epigenome. In the context of this review, we define the epigenome as the chemical compounds and/or proteins that can interact with nuclear DNA to direct the
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Data now indicates that in addition to genetic alterations/mutations, human cancer cells exhibit important changes in their epigenome. In the context of this review, we define the epigenome as the chemical compounds and/or proteins that can interact with nuclear DNA to direct the specific and localized activation or silencing of genes to control the production of cellular proteins (directly or indirectly) in a given cell. Our ever-growing knowledge of how the epigenome can affect cellular processes has largely changed our view of cancer being a solely genetic disease. Nowadays, cancer is largely defined and characterized by the dynamic changes in both the genome and epigenome, which function together and contribute concomitantly to cancer initiation and progression. Since epigenetic modifications are crucial processes involved in controlling cellular identity and lineage fate, perturbations in this layer of gene regulation can contribute to the acquisition of new cellular characteristics different than those that were “initially” intended. For example, aberrant epigenetic alterations may transform normal non-cancer cells into cancer stem cells (CSCs), endowing them with the loss of differentiation and the acquisition of stem-like characteristics. In this review, we will focus our discussion on CSCs in the context of pancreatic ductal adenocarcinoma (PDAC). We will discuss how different epigenetic modifications create a landscape that can impact CSC identity and the way this small sub-population of cells contributes to tumor initiation, progression, and resistance to therapy. Moreover, we will highlight the latest discoveries in epigenetic-based therapies as a means of targeting CSCs. Full article
(This article belongs to the Special Issue Epigenetics of Pancreatic Cancer)
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Open AccessReview Epigenetic Targeting of Aberrant Transcriptional Modulation in Pancreatic Cancer
Received: 7 May 2018 / Revised: 25 May 2018 / Accepted: 28 May 2018 / Published: 31 May 2018
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Abstract
While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. Late diagnosis and resistance to conventional therapies contribute to high mortality rates in spite of the remarkable recent advances
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While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. Late diagnosis and resistance to conventional therapies contribute to high mortality rates in spite of the remarkable recent advances in cancer management and research. Consequently, there is an urgent need to find new and unconventional therapeutic targets to improve prognosis and survival of pancreatic cancer patients. In this review, we discuss the transcriptional effects of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal domain (BET) and Histone Deacetylase (HDAC) inhibitors, which are currently highly promising therapeutic options. We suggest that these inhibitors can be better utilized at lower doses which exploit their transcriptional modulatory effects on pancreatic cancer transcriptional programs directed by specific factors such as MYC and Forkhead Box A1 (FOXA1), rather than simply based on their anti-proliferative effects. This approach can potentially help avoid the intolerable adverse events frequently elicited by the use of these treatments at higher doses. In particular, we underscore the crucial role of distal regulatory elements in mediating the specific effects of these epigenetic inhibitors and propose using them in a more selective and prudent manner. Full article
(This article belongs to the Special Issue Epigenetics of Pancreatic Cancer)
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