Special Issue "Genome Dynamics in Pancreatic Cancer Biology and Therapy"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 31 March 2021.

Special Issue Editors

Prof. Dr. Albrecht Neesse
Website
Guest Editor
Department of Gastroenterology and gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany
Interests: pancreatic cancer; tumor microenvironment; drug delivery; genome dynamics
Dr. Elisabeth Hessmann
Website
Guest Editor
Department of Gastroenterology and gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany
Interests: pancreatic cancer; chromatin regulation; transcription

Special Issue Information

Dear Colleagues,

We are delighted to invite you to contribute to a Special Issue of Cells titled “Genome Dynamics in Pancreatic Cancer Biology and Therapy”.

Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine with a desperate need to develop better treatment strategies. In fact, despite significant research efforts, PDAC still displays the highest mortality rate among all solid tumors in mankind. Major causes for its devastating disease outcome are the exceptionally aggressive tumor biology and the remarkable resistance to conventional anti-tumor treatments. Compelling evidence exists that both characteristics are univocally driven by disturbed genome dynamics—e.g., defects in genomic stability or altered chromatin regulation and transcription. For instance, complex interactions between tumor cells and cells from the surrounding microenvironment are orchestrated by epigenetic mechanisms that critically shape cell plasticity and chemoresistance. Consequently, elucidating the molecular underpinnings and the therapeutic consequences of altered genome dynamics in the different tumor compartments in PDAC biology and treatment will provide novel avenues to combat this dismal disease.

This Special Issue of Cells aims to understand how altered genome dynamics drive PDAC development, progression, and therapy resistance and will aid in revealing novel translational strategies exploring the potential of targeting genome dynamics in PDAC treatment.

We are looking forward to your contributions to this Special Issue.

Prof. Dr. Albrecht Neesse
Dr. Elisabeth Hessmann
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 papers will be 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. Cells is an international peer-reviewed open access monthly 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 2000 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 cancer
  • genome dynamics
  • transcription
  • chromatin regulation
  • therapy resistance
  • tumorstroma interaction
  • heterogeneity

Published Papers (3 papers)

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Research

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Open AccessArticle
RNA Extraction from Endoscopic Ultrasound-Acquired Tissue of Pancreatic Cancer Is Feasible and Allows Investigation of Molecular Features
Cells 2020, 9(12), 2561; https://doi.org/10.3390/cells9122561 - 30 Nov 2020
Abstract
Transcriptome analyses allow the distinguishing of pancreatic ductal adenocarcinoma (PDAC) subtypes, exhibiting different prognoses and chemotherapy responses. However, RNA extraction from pancreatic tissue is cumbersome and has been performed mainly from surgical samples, which are representative of < 20% of cases. The majority [...] Read more.
Transcriptome analyses allow the distinguishing of pancreatic ductal adenocarcinoma (PDAC) subtypes, exhibiting different prognoses and chemotherapy responses. However, RNA extraction from pancreatic tissue is cumbersome and has been performed mainly from surgical samples, which are representative of < 20% of cases. The majority of PDAC patients undergo endoscopic ultrasound (EUS)-guided tissue acquisition (EUS-TA), but RNA has been rarely extracted from EUS-TA with scanty results. Herein, we aimed to determine the best conditions for RNA extraction and analysis from PDAC EUS-TA samples in order to carry out molecular analyses. PDAC cases underwent diagnostic EUS-TA, with needles being a 25G fine needle aspiration (FNA) in all patients and then either a 20G lateral core-trap fine needle biopsy (FNB) or a 25G Franseen FNB; the conservation methods were either snap freezing, RNALater or Trizol. RNA concentration and quality (RNA integrity index; RIN) were analyzed and a panel of genes was investigated for tissue contamination and markers of molecular subtype and aggressivity through qRT-PCR. Seventy-four samples from 37 patients were collected. The median RNA concentration was significantly higher in Trizol samples (10.33 ng/uL) compared with snap frozen (0.64 ng/uL; p < 0.0001) and RNALater (0.19 ng/uL; p < 0.0001). The RIN was similar between Trizol (5.15) and snap frozen samples (5.85), while for both methods it was higher compared with RNALater (2.7). Among the needles, no substantial difference was seen in terms of RNA concentration and quality. qRT-PCR analyses revealed that samples from all needles were suitable for the detection of PDAC subtype markers (GATA6 and ZEB1) and splice variants associated with mutational status (GAP17) as well as for the detection of contaminating tissue around PDAC cells. This is the first study that specifically investigates the best methodology for RNA extraction from EUS-TA. A higher amount of good quality RNA is obtainable with conservation in Trizol with a clear superiority of neither FNA nor FNB needles. RNA samples from EUS-TA are suitable for transcriptome analysis including the investigation of molecular subtype and splice variants expression. Full article
(This article belongs to the Special Issue Genome Dynamics in Pancreatic Cancer Biology and Therapy)
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Open AccessArticle
Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy
Cells 2020, 9(9), 2110; https://doi.org/10.3390/cells9092110 - 16 Sep 2020
Abstract
Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline BRCA1/2-mutated PDAC patients [...] Read more.
Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline BRCA1/2-mutated PDAC patients after platinum-based induction for the first time. Transferability of such a concept to other DNA damage response (DDR) genes remains unclear. Here, we conducted a placebo-controlled, three-armed preclinical trial to evaluate the efficacy of multi-DDR interference (mDDRi) as maintenance therapy vs. continuous FOLFIRINOX treatment, implemented with orthotopically transplanted ATM-deficient PDAC cell lines. Kaplan–Meier analysis, cross-sectional imaging, histology, and in vitro analysis served as analytical readouts. Median overall survival was significantly longer in the mDDRi maintenance arm compared to the maintained FOLFIRINOX treatment. This survival benefit was mirrored in the highest DNA-damage load, accompanied by superior disease control and reduced metastatic burden. In vitro analysis suggests FOLFIRINOX-driven selection of invasive subclones, erased by subsequent mDDRi treatment. Collectively, this preclinical trial substantiates mDDRi in a maintenance setting as a novel therapeutic option and extends the concept to non-germline BRCA1/2-mutant PDAC. Full article
(This article belongs to the Special Issue Genome Dynamics in Pancreatic Cancer Biology and Therapy)
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Review

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Open AccessReview
Coming in the Air: Hypoxia Meets Epigenetics in Pancreatic Cancer
Cells 2020, 9(11), 2353; https://doi.org/10.3390/cells9112353 - 25 Oct 2020
Abstract
With a five-year survival rate under 9%, pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest tumors. Although the treatment options are slightly improving, PDAC is the second leading cause of cancer related death in 2020 in the US. In addition to a [...] Read more.
With a five-year survival rate under 9%, pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest tumors. Although the treatment options are slightly improving, PDAC is the second leading cause of cancer related death in 2020 in the US. In addition to a pronounced desmoplastic stroma reaction, pancreatic cancer is characterized by one of the lowest levels of oxygen availability within the tumor mass and these hypoxic conditions are known to contribute to tumor development and progression. In this context, the major hypoxia associated transcription factor family, HIF, regulates hundreds of genes involved in angiogenesis, metabolism, migration, invasion, immune escape and therapy resistance. Current research implications show, that hypoxia also modulates diverse areas of epigenetic mechanisms like non-coding RNAs, histone modifications or DNA methylation, which cooperate with the hypoxia-induced transcription factors as well as directly regulate the hypoxic response pathways. In this review, we will focus on hypoxia-mediated epigenetic alterations and their impact on pancreatic cancer. Full article
(This article belongs to the Special Issue Genome Dynamics in Pancreatic Cancer Biology and Therapy)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Targeting HDACs in Pancreatic Neuroendocrine Tumor Models
Authors: Rosa Lynn Schmitz*; Julia Weißbach*; Jan Kleilein; Patricia Grabowski; Patrick Michl; Jörg Schrader*; Sebastian Krug*
Affiliation: University Hospital Halle (Saale), Dept. of Internal Medicine I, Germany University Hospital Charite Berlin, Dept. of Gastroenterology, Germany University Hospital Hamburg-Eppendorf, Dept. of Gastroenterology, Germany
Abstract: Purpose: Compared to common pancreatic adenocarcinomata (PDAC), pancreatic neuroendocrine tumors (PanNET) represent a rare and heterogeneous tumor entity. In addition to surgical resection, several therapeutic approaches including biotherapy, targeted therapy or chemotherapy are applicable. However, primary or secondary resistance to current therapies is still challenging. Recent genome-wide sequencing efforts in PanNET identified a large number of mutations in pathways involved in epigenetic modulation including acetylation. Therefore, targeting epigenetic modulators in neuroendocrine cells could be a new therapeutic avenue. Detailed information on functional effects and affected signaling pathways upon epigenetic targeting in PanNETs, however, is missing. Methods: The primary human PanNET cells NT-3 and NT-18 as well as the murine insulinoma cell lines beta-TC-6 (mouse) and RIN-T3 (rat) were treated with the non-selective HDAC-Inhibitor Panobinostat (PB) and analyzed for functional effects and affected signaling pathways performing Western blot, FACS and qPCR analyses. Additionally, NanoString analyses of more than 500 potentially affected targets were performed. The impact of PB was validated in-vivo investigating IHC analyses on samples from human PanNET patients and the transgenic neuroendocrine Rip1Tag2-mouse model. Results: In addition to hyper-acetylation of known targets, PB dose-dependently induced cell cycle arrest and apoptosis in neuroendocrine cells from various species. Interestingly, the effect of PB was associated with alterations in the SOCS3/p-STAT3/JAK signaling. The modulation of HDAC6 by PB had a central role in this context. Furthermore, HDAC inhibition stimulated re-differentiation of human primary PanNET cells by increasing mRNA-expression of SSTRs and insulin production. SOCS3/pSTAT3 and HDAC6 expression was also present in RIP1Tag mouse and human PanNET samples. Conclusions: Our results uncover epigenetic HDAC modulation using PB as promising new therapeutic avenue in PanNET linking inflammatory pathways such as SOCS3/p-STAT3/JAK signaling to epigenetic targeting. Based on our in-vitro data, the impact of HDAC inhibition on SOCS3/p-STAT3/JAK signaling and HDAC-subtype specificity warranted further validation in-vivo.

Title: Epigenetic regulation of tumor-stroma crosstalk in pancreatic cancer- Recent advances
Authors: Kim C. Honselmann; Louisa Bolm; Andrew S. Liss
Affiliation: 1Department of Surgery, University Medical Center Schleswig-Holstein, Campus Luebeck, Germany 2Pancreatic Biology Laboratory, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, USA
Abstract: The hallmark of pancreatic ductal adenocarcinoma (PDAC) is an abundant desmoplastic reaction, predominantly composed of activated cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), that surrounds the cancer cells. This stroma can make up to 70% of the tumor volume and just because its sheer abundance, tumor-stromacell crosstalk is highly probable and responsible for at least some of the aggressive biology of PDAC. Unfortunately, targeting of the stroma has not led to clinically relevant survival benefits for patients as initially hoped for. The stroma is a dynamic entity that can arise from quiescent pancreatic stellate cells as well as other cell types. These cancer-associated fibroblasts can then produce components of the extracellular matrix and induce epithelial- to mesenchymal transition. These dynamic changes in the behavior and morphology of CAFs and cancer cells suggest that epigenetic changes are involved, possibly presenting another therapeutic target of action. In this review, we will summarize the recent evidence for epigenetic regulation by DNA methylation and histone modification of tumor-stroma crosstalk dependent cell signaling pathways in cancer with an emphasis on PDAC.

Title: Feasibility and Optimization of RNA extraction from EUS-acquired tissue in Pancreatic Cancer
Authors: Livia Archibugi; Valentina Panzeri; Miriam Redegalli; Sabrina Gloria Giulia Testoni; Veronica Ruta; Maria Chiara Petrone; Gemma Rossi; Massimo Falconi; Michele Reni; Chiara Naro; Claudio Doglioni; Claudio Sette; Paolo Giorgio Arcidiacono; Gabriele Capurso
Affiliation: 1. Pancreato-Biliary Endoscopy and Endosonography Division, Vita-Salute San Raffaele University Milan, Italy, IRCCS San Raffaele Scientific Institute, Milan, Italy 2. Department of Neuroscience, Section of Human Anatomy, Università Cattolica del Sacro Cuore, Rome, Italy; 3. IRCCS Fondazione Policlinico Agostino Gemelli, Rome, Italy 4. Pathology Department, Vita-Salute San Raffaele University Milan, Italy, IRCCS San Raffaele Scientific Institute, Milan, Italy 5. Pancreatic Surgery Unit, Vita-Salute San Raffaele University Milan, Italy, IRCCS San Raffaele Scientific Institute, Milan, Italy 6. Oncology Unit, Vita-Salute San Raffaele University Milan, Italy, IRCCS San Raffaele Scientific Institute, Milan, Italy
Abstract: Purpose: Pancreatic ductal adenocarcinoma (PDAC) is the 2nd leading cause of cancer-related mortality. Transcriptome analyses have allowed to distinguish PDAC subtypes exhibiting different prognosis and chemotherapy response. However, RNA extraction from pancreatic tissue is cumbersome and has been performed mainly on surgical samples, representative of <20% of cases. The majority of PDAC patients undergo Endoscopic UltraSound (EUS)-guided tissue acquisition (EUS-TA), but RNA has been rarely extracted from EUS-TA with scanty results. Our aim was to determine the best conditions for RNA extraction and analysis from EUS-TA of PDAC patients in order to determine the molecular subtype. Methods: PDAC cases underwent diagnostic EUS-TA, with needles being 25G FNA in all patients and then either 20G lateral core-trap FNB or 25G Franseen FNB; the conservation methods were either snap freezing, RNALater or Trizol. RNA concentration and quality (RNA Integrity Index; RIN) were analyzed and a panel of genes investigated for molecular subtype identification. Results: 74 samples from 37 patients were collected. Median RNA concentration was significantly higher in Trizol samples (10,330 pg/ul) compared to snap frozen (637 pg/ul;p<0.0001) or RNALater (190.5 pg/ul;p<0.0001). RIN was similar between Trizol samples (5.15) and snap frozen samples (5.85;p=0.8), while both methods were borderline significantly higher compared to RNALater (2.7;p=0.07 for snap frozen and p=0.08 for Trizol). Among needles, no significant difference was seen in terms of concentration and RIN but the 25G Franseen FNB was able to retrieve a RIN above 5 in 83% of cases. q-RT-PCR analyses of PDAC subtype markers indicated that RNA samples from EUS-TA are suitable for transcriptome analysis. Conclusions: This is the first study that specifically investigates the best methodology for RNA extraction from EUT-TA. A great amount of good quality RNA is obtainable from EUS-TA samples in Trizol; 25G Franseen FNB needles might give some benefit. The analyses to verify the possibility to identify PDAC molecular subtypes in these samples are ongoing.

Title: Nuclear dynamics in pancreatic cancer, implications for gene expression
Authors: Luis F. Flores; Brooke R. Tader; Martin E. Fernandez-Zapico
Affiliation: Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA
Abstract: Changes in nuclear shape have been extensively associated with cancer cells. In most normal cells, nuclei have a regular ellipsoid shape, but an irregular nuclear contour has been seen in cancer cells. Furthermore, alterations in nuclear morphology have been well characterized and have become the ‘gold standard’ for tumor staging and grading. However, there has been no mechanistic link established between oncogenic transformation and disruption of nuclear morphology. The emergence of aberrant nuclei in many cancers is well documented and Pancreatic Ductal Adenocarcinoma (PDAC) is no exception as there are various cytological features that are scored and used for predicting PDAC. These cytological studies include analysis of nuclear morphology and have proven to be a useful marker for prognosis and diagnosis. Nuclear morphology may be a simple readout, but the implications it can have on cell biology are profound. Studies have shown that simply growing a cell on differently shaped substrates resulted in differences in actomyosin activity, transcription factor shuttling, and gene expression . In PDAC cells, mutant KRAS induces PDAC nuclei compaction and increases the stability of nuclear lamina proteins and enrichment of repressive marks in the nuclear periphery. Thus, in a cancer background, aberrant nuclear morphology is a topic that must continue to be rigorously investigated. Here, we aim to highlight and discuss the factors that regulate nuclear morphology and their implications in PDAC.

Title: Identification of an NFATc1-EZH2 axis in pancreatic cancer progression
Authors: Albrecht Neesse; Elisabeth Heßmann
Affiliation: Department of Gastroenterology and gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany

Title: Coming in the air: hypoxia meets epigenetics in pancreatic cancer
Authors: Claudia Geismann 1; Alexander Arlt 2,*
Affiliation: 1 Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany; [email protected] 2 Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany; [email protected] * Correspondence: [email protected]; Tel.: +0049-431-50022210
Abstract: With a 5 year survival rate under 9%, pancreatic adenocarcinoma (PDAC) represents one of the deadliest tumors. Although the treatment options are slightly improving, PDAC is the second leading cause of cancer related diseases in 2020 in the US. In addition to a pronounced desmoplastic stroma reaction, pancreatic cancer is characterized by one of the lowest levels of oxygen availability within the tumor mass and these hypoxic conditions are known to contribute to tumor development and progression. In this context, the major hypoxia associated transcription factor family, HIF, regulates hundreds of genes involved in angiogenesis, metabolism, migration, invasion, immune escape and therapy resistance. Current research implication show, that hypoxia also modulates diverse areas of epigenetic mechanisms like non-coding RNAs, histone modifications or DNA methylation, which cooperate with the hypoxia induced transcription factors as well as directly regulate the hypoxic response pathways. In this review, we will focus on hypoxia mediated epigenetic alterations and their impact on pancreatic cancer.

Title: Maintenance therapy for ATM-deficient pancreatic cancer by multiple DNA damage response interference after platinum-based chemotherapy
Authors: Elodie Roger; Johann Gout; Frank Arnold; Alica K. Beutel; Martin Müller; Alireza Abaei; Thomas F.E. Barth; Volker Rasche; Thomas Seufferlein; Lukas Perkhofer; Alexander Kleger
Affiliation: Ulm University, Ulm, Germany
Abstract: Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancies albeit PDAC-related death is projected rising over the next decade. Recently maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline BRCA1/2-mutated PDAC patients after platinum-based induction for the first time. Transferability of such a concept to other DNA damage response (DDR) genes like ATM remains unclear. In this preclinical trial we could prove effectivity of a multi-DDR interference (mDDRi) with PARP, ATR, and DNA-PKcs inhibitors in an ATM-deficient murine PDAC model. The use of mDDRi as a maintenance therapy after induction with FOLFIRINOX resulted in this placebo-controlled, three-armed preclinical trial in a significant survival benefit compared to the standard of care chemotherapy with FOLFIRINOX, that was accompanied by a significant reduction of the metastatic load. The trial presented sets the basis for further clinical evaluation e.g. in a first early clinical trial setting.

Title: Leveraging Subtype-specific Transcribed Enhancer Programs in Pancreatic Cancer Therapy: STEPs Toward Mechanism-Based Individualized Medicine
Authors: Feda H. Hamdan; Steven A. Johnsen
Affiliation: Gene Regulatory Mechanisms and Molecular Epigenetics Lab, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
Abstract: Individualized medicine approaches hold significant promise for managing notoriously aggressive malignancies such as pancreatic cancer. Recent breakthroughs including molecular subtyping of pancreatic cancer, development of cutting-edge molecular techniques, and the availability of clinically relevant experimental systems such as organoids and patient-derived xenografts allow for major advancements in tailored therapy. Particularly aggressive molecular subtypes of pancreatic cancer, namely the basal subtype, exhibit an aberrant activation of a subtype-specific enhancer program largely responsible for the activation of detrimental genes. Molecular observations in other systems revealed that numerous enhancers produce transcribed constructs called enhancer RNAs (eRNAs), the function of which is still under investigation. Additionally, 3D chromatin characterization showed that enhancers can specifically regulate transcription of different target genes via context-specific interaction patterns which can be modulated and perturbed. In this conceptual report, we integrate the major and most recent molecular findings in different systems to suggest mechanism-based individualized therapy approaches aiming to improve pancreatic cancer patient prognosis. We propose that the analysis and targeting of Subtype-specific Transcribed Enhancer Programs (STEPs) will not only lead to optimized therapy of pancreatic cancer but also enable more precise monitoring of therapeutic responsiveness in a rapid and accurate manner. Coupling complex molecular modalities to direct translational medicine is crucial to developing effective therapy in pancreatic cancer and other diseases with particularly low survival rates.

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