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Cancers
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Tumor Heterogeneity in Pancreatic Cancer
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Tumor Heterogeneity in Pancreatic Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (1 November 2021) | Viewed by 9233

Special Issue Editor

Prof. Volker Ellenrieder

E-Mail Website
Guest Editor
University of Gottingen
Interests: Pancreatic Cancer

Special Issue Information

Dear Colleagues,

With a 5-year survival rate of less than 10%, pancreatic cancer is among the cancers with the worst prognoses. According to recent studies, pancreatic cancer will probably be the second most common cause of cancer-related death in Western countries within the next 5–10 years. From a clinical point of view, the infaust prognosis mainly results from the particularly aggressive tumor growth with early infiltration into surrounding structures, the pronounced invasiveness, the high recurrence rate after resection and the high resistance to chemotherapy. The aggressive biological behavior and pronounced chemoresistance are causally related to the high genetic and molecular intra- and intertumoral heterogeneity.

Extensive genome-wide analyses over the last 10 years have fundamentally expanded our understanding in oncology in general and in pancreatic cancer as well. A key finding of these investigations is the knowledge of genetic and molecular subtypes that shape the biological and clinical behavior of the tumor and provide new therapeutic options. In pancreatic carcinoma, different genetically and molecularly defined subtypes apparently have important roles in both the development and progression of pancreatic cancer and in mediating resistance to therapy.

This Special Issue focuses on the relevance of molecular and genetic heterogeneity in pancreatic carcinoma for the clinical course of the disease, especially in the processes of growth, tumor cell invasion and mediation of treatment resistance. Thereby, subtype-specific mechanisms, cellular interactions and therapeutic vulnerabilities will be the focus of the contributions.

Prof. Volker Ellenrieder
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. 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.

Published Papers (3 papers)

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Research

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22 pages, 7854 KiB  
Article
TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer
by Lennart Versemann, Shilpa Patil, Benjamin Steuber, Zhe Zhang, Waltraut Kopp, Hannah Elisa Krawczyk, Silke Kaulfuß, Bernd Wollnik, Philipp Ströbel, Albrecht Neesse, Shiv K. Singh, Volker Ellenrieder and Elisabeth Hessmann
Cancers 2022, 14(14), 3451; https://doi.org/10.3390/cancers14143451 - 15 Jul 2022
Cited by 5 | Viewed by 2126
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) represents a lethal malignancy with a consistently poor outcome. Besides mutations in PDAC driver genes, the aggressive tumor biology of the disease and its remarkable therapy resistance are predominantly installed by potentially reversible epigenetic dysregulation. However, epigenetic regulators act [...] Read more.
Pancreatic Ductal Adenocarcinoma (PDAC) represents a lethal malignancy with a consistently poor outcome. Besides mutations in PDAC driver genes, the aggressive tumor biology of the disease and its remarkable therapy resistance are predominantly installed by potentially reversible epigenetic dysregulation. However, epigenetic regulators act in a context-dependent manner with opposing implication on tumor progression, thus critically determining the therapeutic efficacy of epigenetic targeting. Herein, we aimed at exploring the molecular prerequisites and underlying mechanisms of oncogenic Enhancer of Zeste Homolog 2 (EZH2) activity in PDAC progression. Preclinical studies in EZH2 proficient and deficient transgenic and orthotopic in vivo PDAC models and transcriptome analysis identified the TP53 status as a pivotal context-defining molecular cue determining oncogenic EZH2 activity in PDAC. Importantly, the induction of pro-apoptotic gene signatures and processes as well as a favorable PDAC prognosis upon EZH2 depletion were restricted to p53 wildtype (wt) PDAC subtypes. Mechanistically, we illustrate that EZH2 blockade de-represses CDKN2A transcription for the subsequent posttranslational stabilization of p53wt expression and function. Together, our findings suggest an intact CDKN2A-p53wt axis as a prerequisite for the anti-tumorigenic consequences of EZH2 depletion and emphasize the significance of molecular stratification for the successful implementation of epigenetic targeting in PDAC. Full article
(This article belongs to the Special Issue Tumor Heterogeneity in Pancreatic Cancer)
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22 pages, 5953 KiB  
Article
HSP90 Inhibition Synergizes with Cisplatin to Eliminate Basal-like Pancreatic Ductal Adenocarcinoma Cells
by Katharina M. Ewers, Shilpa Patil, Waltraut Kopp, Jürgen Thomale, Tabea Quilitz, Anna Magerhans, Xin Wang, Elisabeth Hessmann and Matthias Dobbelstein
Cancers 2021, 13(24), 6163; https://doi.org/10.3390/cancers13246163 - 07 Dec 2021
Cited by 7 | Viewed by 2603
Abstract
To improve the treatment of pancreatic ductal adenocarcinoma (PDAC), a promising strategy consists of personalized chemotherapy based on gene expression profiles. Investigating a panel of PDAC-derived human cell lines, we found that their sensitivities towards cisplatin fall in two distinct classes. The platinum-sensitive [...] Read more.
To improve the treatment of pancreatic ductal adenocarcinoma (PDAC), a promising strategy consists of personalized chemotherapy based on gene expression profiles. Investigating a panel of PDAC-derived human cell lines, we found that their sensitivities towards cisplatin fall in two distinct classes. The platinum-sensitive class is characterized by the expression of GATA6, miRNA-200a, and miRNA-200b, which might be developable as predictive biomarkers. In the case of resistant PDAC cells, we identified a synergism of cisplatin with HSP90 inhibitors. Mechanistic explanations of this synergy include the degradation of Fanconi anemia pathway factors upon HSP90 inhibition. Treatment with the drug combination resulted in increased DNA damage and chromosome fragmentation, as we have reported previously for ovarian cancer cells. On top of this, HSP90 inhibition also enhanced the accumulation of DNA-bound platinum. We next investigated an orthotopic syngeneic animal model consisting of tumors arising from KPC cells (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre, C57/BL6 genetic background). Here again, when treating established tumors, the combination of cisplatin with the HSP90 inhibitor onalespib was highly effective and almost completely prevented further tumor growth. We propose that the combination of platinum drugs and HSP90 inhibitors might be worth testing in the clinics for the treatment of cisplatin-resistant PDACs. Full article
(This article belongs to the Special Issue Tumor Heterogeneity in Pancreatic Cancer)
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Review

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20 pages, 1514 KiB  
Review
Heterogeneity in Pancreatic Cancer Fibroblasts—TGFβ as a Master Regulator?
by Dale M. Watt and Jennifer P. Morton
Cancers 2021, 13(19), 4984; https://doi.org/10.3390/cancers13194984 - 04 Oct 2021
Cited by 9 | Viewed by 3883
Abstract
Pancreatic ductal adenocarcinoma is an aggressive disease for which there are very few available therapies. It is notable for its high degree of tumour complexity, with the tumour microenvironment often accounting for the majority of the tumour volume. Until recently, the biology of [...] Read more.
Pancreatic ductal adenocarcinoma is an aggressive disease for which there are very few available therapies. It is notable for its high degree of tumour complexity, with the tumour microenvironment often accounting for the majority of the tumour volume. Until recently, the biology of the stroma was poorly understood, particularly in terms of heterogeneity. Recent research, however, has shed light on the intricacy of signalling within the stroma and particularly the molecular and functional heterogeneity of the cancer associated fibroblasts. In this review, we summarise the recent improvements in our understanding of the different fibroblast populations within PDAC, with a focus on the role TGFβ plays to dictate their formation and function. These studies have highlighted some of the reasons for the failure of trials targeting the tumour stroma, however, there are still considerable gaps in our knowledge, and more work is needed to make effective fibroblast targeting a reality in the clinic. Full article
(This article belongs to the Special Issue Tumor Heterogeneity in Pancreatic Cancer)
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