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Pancreatic Cancer: From Molecular Basis to Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 15785

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Special Issue Editors

Dr. Enza Lonardo

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Guest Editor

Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ (IGB), CNR, Via Pietro Castellino 111, 80131 Naples, Italy
Interests: 3D cancer models; pancreatic cancer; colorectal cancer; tumor microenvironment; TGFb
Special Issues, Collections and Topics in MDPI journals

Dr. Loretta L. del Mercato

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Guest Editor

CNR-Institute of Nanotechnology, c/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy
Interests: optical pH and oxygen sensors; 3D in vitro tumor models; tumor microenvironment; cell metabolism; cell–cell interactions; fluorescence live cell imaging; scientific computing and data processing
Special Issues, Collections and Topics in MDPI journals

Dr. Bruno Sainz

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Guest Editor

Department of Cancer Biology, Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM), 28029 Madrid, Spain
Interests: cancer; cancer stem cells; cancer immunology; tumor microenvironment; virology

Special Issue Information

Dear Colleagues,

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancer and the seventh leading cause of cancer-related deaths worldwide. The molecular biology of PDAC is still poorly comprehended; nevertheless, newly noteworthy improvements have been made with the identification of molecular subtypes. Molecular subtypes pilot preclinical and clinical studies and treatment in several cancer types. The power to predict ideal therapeutic strategies improves overall patient outcomes, reducing treatment-linked morbidity and cost. While treatment strategies based on histopathological criteria supported by strong data are well proven in many cancer types, subtypes of PDAC are not currently used for treatment decisions. Yet, increasing molecular data are outlining subgroups in PDAC with different biology and potential precise therapeutic susceptibilities, offering the chance to describe a novel clinically valid molecular taxonomy.

This Special Issue aims to shed light on current knowledge regarding the molecular subtyping of PDAC and unravel forthcoming approaches for using a molecular taxonomy to guide therapeutic advance and conventional therapy with the overall goal of improving outcomes for this disease.

We warmly welcome submissions, including original papers and reviews, on this widely discussed topic.

Dr. Enza Lonardo
Dr. Loretta L. del Mercato
Dr. Bruno Sainz
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 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

molecular subtypes
tumor compartments
targeted therapy
in vitro 3D cultures
histopathology
tumor microenvironment
cellular plasticity
resistance
genetics

Published Papers (4 papers)

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Research

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15 pages, 2968 KiB

Open AccessArticle

Gemcitabine-Based Chemoradiotherapy Enhanced by a PARP Inhibitor in Pancreatic Cancer Cell Lines

by Waisse Waissi, Jean-Christophe Amé, Carole Mura, Georges Noël and Hélène Burckel

Int. J. Mol. Sci. 2021, 22(13), 6825; https://doi.org/10.3390/ijms22136825 - 25 Jun 2021

Cited by 8 | Viewed by 3168

Abstract

Pancreatic ductal adenocarcinoma is a devastating disease with a 5-year overall survival of 9% for all stages. Gemcitabine-based chemoradiotherapy for locally advanced pancreatic cancer is highly toxic. We conducted an in vitro study to determine whether poly(ADP-ribose) polymerase-1 inhibition radiosensitized gemcitabine-based chemotherapy. Human pancreatic cancer cell lines, MIA PaCa-2, AsPC-1, BxPC-3 and PANC-1 were treated with gemcitabine (10 nM) and/or olaparib (1 µM). Low-LET gamma single dose of 2, 5 and 10 Gy radiations were carried out. Clonogenic assay, PAR immunoblotting, cell cycle distribution, γH2Ax, necrotic and autophagic cell death quantifications were performed. Treatment with olaparib alone was not cytotoxic, but highly radiosensitized cell lines, particularly at high dose per fraction A non-cytotoxic concentration of gemcitabine radiosensitized cells, but less than olaparib. Interestingly, olaparib significantly enhanced gemcitabine-based radiosensitization in PDAC cell lines with synergistic effect in BxPC-3 cell line. All cell lines were radiosensitized by the combination of gemcitabine and olaparib, through an increase of unrepaired double-strand, a G2 phase block and cell death. Radiosensitization was increased with high dose of radiation. The combination of olaparib with gemcitabine-based chemoradiotherapy could lead to an enhancement of local control in vivo and an improvement in disease-free survival. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Molecular Basis to Therapy)

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Review

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14 pages, 1046 KiB

Open AccessReview

Coagulation Signaling through PAR1 as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma

by Aditi Kothari and Matthew J. Flick

Int. J. Mol. Sci. 2021, 22(10), 5138; https://doi.org/10.3390/ijms22105138 - 12 May 2021

Cited by 6 | Viewed by 2946

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with a 5-year survival rate of less than 10% following diagnosis. The aggressive and invasive properties of pancreatic cancer tumors coupled with poor diagnostic options contribute to the high mortality rate since most patients present with late-stage disease. Accordingly, PDAC is linked to the highest rate of cancer-associated venous thromboembolic disease of all solid tumor malignancies. However, in addition to promoting clot formation, recent studies suggest that the coagulation system in PDAC mediates a reciprocal relationship, whereby coagulation proteases and receptors promote PDAC tumor progression and dissemination. Here, upregulation of tissue factor (TF) by tumor cells can drive local generation of the central coagulation protease thrombin that promotes cell signaling activity through protease-activated receptors (PARs) expressed by both tumor cells and multiple stromal cell subsets. Moreover, the TF-thrombin-PAR1 signaling axis appears to be a major mechanism of cancer progression in general and PDAC in particular. Here, we summarize the current literature regarding the role of PAR1 in PDAC and review possibilities for pharmacologically targeting PAR1 as a PDAC therapeutic approach. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Molecular Basis to Therapy)

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16 pages, 688 KiB

Open AccessReview

Pancreatic Neuroendocrine Neoplasms in Multiple Endocrine Neoplasia Type 1

by Francesca Marini, Francesca Giusti, Francesco Tonelli and Maria Luisa Brandi

Int. J. Mol. Sci. 2021, 22(8), 4041; https://doi.org/10.3390/ijms22084041 - 14 Apr 2021

Cited by 18 | Viewed by 3385

Abstract

Pancreatic neuroendocrine tumors (pNETs) are a rare group of cancers accounting for about 1–2% of all pancreatic neoplasms. About 10% of pNETs arise within endocrine tumor syndromes, such as Multiple Endocrine Neoplasia type 1 (MEN1). pNETs affect 30–80% of MEN1 patients, manifesting prevalently as multiple microadenomas. pNETs in patients with MEN1 are particularly difficult to treat due to differences in their growth potential, their multiplicity, the frequent requirement of extensive surgery, the high rate of post-operative recurrences, and the concomitant development of other tumors. MEN1 syndrome is caused by germinal heterozygote inactivating mutation of the MEN1 gene, encoding the menin tumor suppressor protein. MEN1-related pNETs develop following the complete loss of function of wild-type menin. Menin is a key regulator of endocrine cell plasticity and its loss in these cells is sufficient for tumor initiation. Somatic biallelic loss of wild-type menin in the neuroendocrine pancreas presumably alters the epigenetic control of gene expression, mediated by histone modifications and DNA hypermethylation, as a driver of MEN1-associated pNET tumorigenesis. In this light, epigenetic-based therapies aimed to correct the altered DNA methylation, and/or histone modifications might be a possible therapeutic strategy for MEN1 pNETs, for whom standard treatments fail. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Molecular Basis to Therapy)

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15 pages, 335 KiB

Open AccessReview

Molecular Alterations in Pancreatic Cancer: Transfer to the Clinic

by Yolanda Rodríguez Gil, Paula Jiménez Sánchez, Raúl Muñoz Velasco, Ana García García and Víctor Javier Sánchez-Arévalo Lobo

Int. J. Mol. Sci. 2021, 22(4), 2077; https://doi.org/10.3390/ijms22042077 - 19 Feb 2021

Cited by 7 | Viewed by 5279

Abstract

Pancreatic ductal adenocarcinoma (PDA) is the most common cancer of the exocrine pancreas and probably the tumor that has benefited the least from clinical progress in the last three decades. A consensus has been reached regarding the histologic classification of the ductal preneoplastic lesions (pancreatic intra-epithelial neoplasia—PanIN) and the molecular alterations associated with them. Mutations in KRAS and inactivation of CDKN2A, SMAD4 and TP53 are among the most prevalent alterations. Next generation sequencing studies are providing a broad picture of the enormous heterogeneity in this tumor type, describing new mutations less prevalent. These studies have also allowed the characterization of different subtypes with prognostic value. However, all this knowledge has not been translated into a clinical progress. Effective preventive and early diagnostic strategies are essential to improve the survival rates. The main challenge is, indeed, to identify new effective drugs. Despite many years of research and its limited success, gemcitabine is still the first line treatment of PDA. New drug combinations and new concepts to improve drug delivery into the tumor, as well as the development of preclinical predictive assays, are being explored and provide optimism and prospects for better therapies. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Molecular Basis to Therapy)

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