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Dissecting the Contribution of the Tumor Microenvironment to Pancreatic Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 32434

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Special Issue Editor

Dr. Tracy Putoczki

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Guest Editor

Personalized Oncology Division, The Walter and Eliza Hall Institute of Medical Research
Interests: cancer; cytokines; inflammation; microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Less than 10% of pancreatic cancer patients survive beyond 5 years. This is the most lethal of all cancers, with the majority of patients succumbing to the disease within 6 months. Over the last decade, very few new drugs have been approved for the treatment of this devastating disease, with little improvement in patient outcomes. This reflects our limited understanding of the biology underlying this cancer.

Pancreatic ductal adenocarcinoma is a stroma-rich solid tumour arising from the exocrine compartment of the pancreatic gland. The proposed framework for the progression of the normal epithelium to pancreatic intraepithelial neoplasia (PanIN), which is a non-invasive neoplastic precursor to PDAC, is associated with a series of common histological and genetic alterations. Histological evaluation and staging remain the gold standard in defining the clinical characteristics of PDAC and are a strong prognostic factor. However, targetable drivers underlying phenotypic changes and tumour progression remain elusive.

The current Special Issue invites contributions aimed at exploring the complex bi-directional conversations that occur between cancer cells and their microenvironment. These studies will not only build up our fundamental understanding of the biology of this disease, but will also reveal new therapeutic opportunities that may lead to improved patient outcomes.

Dr. Tracy Putoczki
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.

Keywords

cancer vulnerability
combination therapy
drug discovery
genetic
inflammation
immunotherapy
fibrosis
mouse model
organoid
personalized medicine
sub-type
xenograft

Published Papers (7 papers)

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Research

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14 pages, 2186 KiB

Open AccessArticle

HGF/MET Axis Induces Tumor Secretion of Tenascin-C and Promotes Stromal Rewiring in Pancreatic Cancer

by Chiara Modica, Martina Olivero, Francesca Zuppini, Melissa Milan, Cristina Basilico and Elisa Vigna

Cancers 2021, 13(14), 3519; https://doi.org/10.3390/cancers13143519 - 14 Jul 2021

Cited by 10 | Viewed by 2407

Abstract

Pancreatic ductal adenocarcinoma is an aggressive tumor characterized by the presence of an abundant stromal compartment contributing significantly to the malignant phenotype. Pancreatic stellate cells are peculiar fibroblasts present in the stroma and represent the predominant source of extracellular matrix proteins, pro-inflammatory cytokines, and growth factors, including hepatocyte growth factor (HGF). Exploiting a co-culture system of human pancreatic stellate cells and cancer cells, we demonstrated that fibroblast activation was reduced upon HGF/MET axis inhibition. To unveil the signaling pathways sustaining stroma modulation orchestrated by MET activation in the tumor, we analyzed the gene expression profile in pancreatic cancer cells stimulated with HGF and treated with HGF/MET inhibitors. Transcriptome analysis showed that, among all the genes modulated by HGF, a subset of 125 genes was restored to the basal level following treatment with the inhibitors. By examining these genes via ingenuity pathway analysis, tenascin C emerged as a promising candidate linking MET signaling and tumor microenvironment. MET-dependent tenascin C modulation in pancreatic cancer cells was validated at RNA and protein levels both in vitro and in vivo. In conclusion, this work identifies tenascin C as a gene modulated by MET activation, suggesting a role in MET-mediated tumor-stroma interplay occurring during pancreatic tumor progression. Full article

(This article belongs to the Special Issue Dissecting the Contribution of the Tumor Microenvironment to Pancreatic Cancer)

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Review

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21 pages, 14619 KiB

Open AccessReview

PRMT5: An Emerging Target for Pancreatic Adenocarcinoma

by Michael K. C. Lee, Sean M. Grimmond, Grant A. McArthur and Karen E. Sheppard

Cancers 2021, 13(20), 5136; https://doi.org/10.3390/cancers13205136 - 13 Oct 2021

Cited by 10 | Viewed by 5792

Abstract

The overall survival of pancreatic ductal adenocarcinoma (PDAC) remains poor and its incidence is rising. Targetable mutations in PDAC are rare, thus novel therapeutic approaches are needed. Protein arginine methyltransferase 5 (PRMT5) overexpression is associated with worse survival and inhibition of PRMT5 results in decreased cancer growth across multiple cancers, including PDAC. Emerging evidence also suggests that altered RNA processing is a driver in PDAC tumorigenesis and creates a partial dependency on this process. PRMT5 inhibition induces altered splicing and this vulnerability can be exploited as a novel therapeutic approach. Three possible biological pathways underpinning the action of PRMT5 inhibitors are discussed; c-Myc regulation appears central to its action in the PDAC setting. Whilst homozygous MTAP deletion and symmetrical dimethylation levels are associated with increased sensitivity to PRMT5 inhibition, neither measure robustly predicts its growth inhibitory response. The immunomodulatory effect of PRMT5 inhibitors on the tumour microenvironment will also be discussed, based on emerging evidence that PDAC stroma has a significant bearing on disease behaviour and response to therapy. Lastly, with the above caveats in mind, current knowledge gaps and the implications and rationales for PRMT5 inhibitor development in PDAC will be explored. Full article

(This article belongs to the Special Issue Dissecting the Contribution of the Tumor Microenvironment to Pancreatic Cancer)

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25 pages, 24344 KiB

Open AccessReview

The Diverse Applications of Pancreatic Ductal Adenocarcinoma Organoids

by Ronnie Ren Jie Low, Wei Wen Lim, Paul M. Nguyen, Belinda Lee, Michael Christie, Antony W. Burgess, Peter Gibbs, Sean M. Grimmond, Frédéric Hollande and Tracy L. Putoczki

Cancers 2021, 13(19), 4979; https://doi.org/10.3390/cancers13194979 - 4 Oct 2021

Cited by 8 | Viewed by 6092

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies. While immortalized cancer cell lines and genetically engineered murine models have increased our understanding of PDAC tumorigenesis, they do not recapitulate inter- and intra-patient heterogeneity. PDAC patient derived organoid (PDO) biobanks have overcome this hurdle, and provide an opportunity for the high throughput screening of potential new therapies. This review provides a summary of the PDAC PDO biobanks established to date, and discusses how they have advanced our understanding of PDAC biology. Looking forward, the development of coculturing techniques for specific immune or stromal cell populations will enable a better understanding of the crosstalk that occurs within the tumor microenvironment, and the impact of this crosstalk on treatment response. Full article

(This article belongs to the Special Issue Dissecting the Contribution of the Tumor Microenvironment to Pancreatic Cancer)

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35 pages, 4581 KiB

Open AccessReview

NF-κB and Pancreatic Cancer; Chapter and Verse

by John Silke and Lorraine Ann O’Reilly

Cancers 2021, 13(18), 4510; https://doi.org/10.3390/cancers13184510 - 7 Sep 2021

Cited by 19 | Viewed by 3418

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the world’s most lethal cancers. An increase in occurrence, coupled with, presently limited treatment options, necessitates the pursuit of new therapeutic approaches. Many human cancers, including PDAC are initiated by unresolved inflammation. The transcription factor NF-κB coordinates many signals that drive cellular activation and proliferation during immunity but also those involved in inflammation and autophagy which may instigate tumorigenesis. It is not surprising therefore, that activation of canonical and non-canonical NF-κB pathways is increasingly recognized as an important driver of pancreatic injury, progression to tumorigenesis and drug resistance. Paradoxically, NF-κB dysregulation has also been shown to inhibit pancreatic inflammation and pancreatic cancer, depending on the context. A pro-oncogenic or pro-suppressive role for individual components of the NF-κB pathway appears to be cell type, microenvironment and even stage dependent. This review provides an outline of NF-κB signaling, focusing on the role of the various NF-κB family members in the evolving inflammatory PDAC microenvironment. Finally, we discuss pharmacological control of NF-κB to curb inflammation, focussing on novel anti-cancer agents which reinstate the process of cancer cell death, the Smac mimetics and their pre-clinical and early clinical trials. Full article

(This article belongs to the Special Issue Dissecting the Contribution of the Tumor Microenvironment to Pancreatic Cancer)

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22 pages, 3477 KiB

Open AccessReview

Dynamic Stromal Alterations Influence Tumor-Stroma Crosstalk to Promote Pancreatic Cancer and Treatment Resistance

by Kendelle J. Murphy, Cecilia R. Chambers, David Herrmann, Paul Timpson and Brooke A. Pereira

Cancers 2021, 13(14), 3481; https://doi.org/10.3390/cancers13143481 - 12 Jul 2021

Cited by 12 | Viewed by 3874

Abstract

Many cancer studies now recognize that disease initiation, progression, and response to treatment are strongly influenced by the microenvironmental niche. Widespread desmoplasia, or fibrosis, is fundamental to pancreatic cancer development, growth, metastasis, and treatment resistance. This fibrotic landscape is largely regulated by cancer-associated fibroblasts (CAFs), which deposit and remodel extracellular matrix (ECM) in the tumor microenvironment (TME). This review will explore the prognostic and functional value of the stromal compartment in predicting outcomes and clinical prognosis in pancreatic ductal adenocarcinoma (PDAC). We will also discuss the major dynamic stromal alterations that occur in the pancreatic TME during tumor development and progression, and how the stromal ECM can influence cancer cell phenotype, metabolism, and immune response from a biochemical and biomechanical viewpoint. Lastly, we will provide an outlook on the latest clinical advances in the field of anti-fibrotic co-targeting in combination with chemotherapy or immunotherapy in PDAC, providing insight into the current challenges in treating this highly aggressive, fibrotic malignancy. Full article

(This article belongs to the Special Issue Dissecting the Contribution of the Tumor Microenvironment to Pancreatic Cancer)

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29 pages, 2818 KiB

Open AccessReview

Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Therapeutic Opportunities and Clinical Challenges

by Ashleigh R. Poh and Matthias Ernst

Cancers 2021, 13(12), 2860; https://doi.org/10.3390/cancers13122860 - 8 Jun 2021

Cited by 39 | Viewed by 6036

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of less than 10%. Macrophages are one of the earliest infiltrating cells in the pancreatic tumor microenvironment, and are associated with an increased risk of disease progression, recurrence, metastasis, and shorter overall survival. Pre-clinical studies have demonstrated an unequivocal role of macrophages in PDAC by contributing to chronic inflammation, cancer cell stemness, desmoplasia, immune suppression, angiogenesis, invasion, metastasis, and drug resistance. Several macrophage-targeting therapies have also been investigated in pre-clinical models, and include macrophage depletion, inhibiting macrophage recruitment, and macrophage reprogramming. However, the effectiveness of these drugs in pre-clinical models has not always translated into clinical trials. In this review, we discuss the molecular mechanisms that underpin macrophage heterogeneity within the pancreatic tumor microenvironment, and examine the contribution of macrophages at various stages of PDAC progression. We also provide a comprehensive update of macrophage-targeting therapies that are currently undergoing clinical evaluation, and discuss clinical challenges associated with these treatment modalities in human PDAC patients. Full article

(This article belongs to the Special Issue Dissecting the Contribution of the Tumor Microenvironment to Pancreatic Cancer)

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18 pages, 1819 KiB

Open AccessReview

Does the Microenvironment Hold the Hidden Key for Functional Precision Medicine in Pancreatic Cancer?

by John Kokkinos, Anya Jensen, George Sharbeen, Joshua A. McCarroll, David Goldstein, Koroush S. Haghighi and Phoebe A. Phillips

Cancers 2021, 13(10), 2427; https://doi.org/10.3390/cancers13102427 - 17 May 2021

Cited by 6 | Viewed by 3449

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and no significant improvement in patient survival has been seen in the past three decades. Treatment options are limited and selection of chemotherapy in the clinic is usually based on the performance status of a patient rather than the biology of their disease. In recent years, research has attempted to unlock a personalised treatment strategy by identifying actionable molecular targets in tumour cells or using preclinical models to predict the effectiveness of chemotherapy. However, these approaches rely on the biology of PDAC tumour cells only and ignore the importance of the microenvironment and fibrotic stroma. In this review, we highlight the importance of the microenvironment in driving the chemoresistant nature of PDAC and the need for preclinical models to mimic the complex multi-cellular microenvironment of PDAC in the precision medicine pipeline. We discuss the potential for ex vivo whole-tissue culture models to inform precision medicine and their role in developing novel therapeutic strategies that hit both tumour and stromal compartments in PDAC. Thus, we highlight the critical role of the tumour microenvironment that needs to be addressed before a precision medicine program for PDAC can be implemented. Full article

(This article belongs to the Special Issue Dissecting the Contribution of the Tumor Microenvironment to Pancreatic Cancer)

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