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Cells
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Pancreatic Cancer: From Molecular Mechanisms to Therapeutic Opportunities
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Pancreatic Cancer: From Molecular Mechanisms to Therapeutic Opportunities

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

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 22925

Special Issue Editors

Dr. Haoqiang Ying

E-Mail Website
Guest Editor
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: cancer biology; cancer therapy; pancreatic cancer; oncogene
Dr. Wantong Yao

E-Mail Website
Guest Editor
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: cancer biology; pancreatic cancer; surfaceome

Special Issue Information

Dear Colleagues,

Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal, and there is a desperate need to develop better treatment strategies. Despite significant research efforts, PDAC still displays the highest mortality rate among all human solid tumors. PDAC is notoriously resistant to both conventional chemotherapy and immune-checkpoint therapies. On the other hand, no effective targeted therapy has ever shown meaningful success in PDAC. The genetic landscape of human PDAC is dominated by oncogenic KRAS mutations, which occur in over 90% of tumors. The KRAS oncogene has been regarded as ‘un-druggable’ for the past three decades. However, over the past decade, especially during the past five years, we have witnessed the development and approval of the first-in-class KRAS inhibitor for G12C mutation. The rapid development of additional KRAS inhibitors, especially the ones targeting G12D mutation which is present in over 30% of human PDAC, is expected to be a game-changer for PDAC treatment and has the potential to dramatically shift the prognosis for many PDAC patients. Nevertheless, based on the clinical observations from the current G12C inhibitor and past targeted therapies, as well as studies on KRAS dependency in preclinical models, rapid development of resistance to KRAS-targeted therapy will be inevitable. Many factors, from genetics to the tumor microenvironment, will likely contribute to the therapeutic resistance. This Special Issue will thus cover the recent progress in the field of pancreatic cancer research, with a special focus on the genetic and molecular heterogeneity, metabolism reprogramming, immune microenvironment and the regulation of KRAS dependency in PDAC. The goal of this Special Issue is to provide an up-to-date overview of PDAC biology and offer perspective on strategies to improve the therapy of this disease.

We are delighted to invite you to contribute to this Special Issue of Cells titled “Pancreatic Cancer: From Molecular Mechanisms to Therapeutic Opportunities”.

Dr. Haoqiang Ying
Dr. Wantong Yao
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. Cells 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 2700 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

  • tumor heterogeneity
  • KRAS-targeted therapy
  • cancer metabolism
  • tumor microenvironment

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Published Papers (6 papers)

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Research

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18 pages, 3073 KiB  
Article
Establishment and Molecular Characterization of Two Patient-Derived Pancreatic Ductal Adenocarcinoma Cell Lines as Preclinical Models for Treatment Response
by Rüdiger Braun, Olha Lapshyna, Jessica Watzelt, Maren Drenckhan, Axel Künstner, Benedikt Färber, Ahmed Ahmed Mohammed Hael, Louisa Bolm, Kim Christin Honselmann, Björn Konukiewitz, Darko Castven, Malte Spielmann, Sivahari Prasad Gorantla, Hauke Busch, Jens-Uwe Marquardt, Tobias Keck, Ulrich Friedrich Wellner and Hendrik Ungefroren
Cells 2023, 12(4), 587; https://doi.org/10.3390/cells12040587 - 11 Feb 2023
Cited by 3 | Viewed by 2279
Abstract
The prognosis of pancreatic ductal adenocarcinoma (PDAC) is exceedingly poor. Although surgical resection is the only curative treatment option, multimodal treatment is of the utmost importance, as only about 20% of tumors are primarily resectable at the time of diagnosis. The choice of [...] Read more.
The prognosis of pancreatic ductal adenocarcinoma (PDAC) is exceedingly poor. Although surgical resection is the only curative treatment option, multimodal treatment is of the utmost importance, as only about 20% of tumors are primarily resectable at the time of diagnosis. The choice of chemotherapeutic treatment regimens involving gemcitabine and FOLFIRINOX is currently solely based on the patient’s performance status, but, ideally, it should be based on the tumors’ individual biology. We established two novel patient-derived primary cell lines from surgical PDAC specimens. LuPanc-1 and LuPanc-2 were derived from a pT3, pN1, G2 and a pT3, pN2, G3 tumor, respectively, and the clinical follow-up was fully annotated. STR-genotyping revealed a unique profile for both cell lines. The population doubling time of LuPanc-2 was substantially longer than that of LuPanc-1 (84 vs. 44 h). Both cell lines exhibited a typical epithelial morphology and expressed moderate levels of CK7 and E-cadherin. LuPanc-1, but not LuPanc-2, co-expressed E-cadherin and vimentin at the single-cell level, suggesting a mixed epithelial-mesenchymal differentiation. LuPanc-1 had a missense mutation (p.R282W) and LuPanc-2 had a frameshift deletion (p.P89X) in TP53. BRCA2 was nonsense-mutated (p.Q780*) and CREBBP was missense-mutated (p.P279R) in LuPanc-1. CDKN2A was missense-mutated (p.H83Y) in LuPanc-2. Notably, only LuPanc-2 harbored a partial or complete deletion of DPC4. LuPanc-1 cells exhibited high basal and transforming growth factor (TGF)-β1-induced migratory activity in real-time cell migration assays, while LuPanc-2 was refractory. Both LuPanc-1 and LuPanc-2 cells responded to treatment with TGF-β1 with the activation of SMAD2; however, only LuPanc-1 cells were able to induce TGF-β1 target genes, which is consistent with the absence of DPC4 in LuPanc-2 cells. Both cell lines were able to form spheres in a semi-solid medium and in cell viability assays, LuPanc-1 cells were more sensitive than LuPanc-2 cells to treatment with gemcitabine and FOLFIRINOX. In summary, both patient-derived cell lines show distinct molecular phenotypes reflecting their individual tumor biology, with a unique clinical annotation of the respective patients. These preclinical ex vivo models can be further explored for potential new treatment strategies and might help in developing personalized (targeted) therapy regimens. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Molecular Mechanisms to Therapeutic Opportunities)
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18 pages, 3250 KiB  
Article
Preliminary Development and Testing of C595 Radioimmunoconjugates for Targeting MUC1 Cancer Epitopes in Pancreatic Ductal Adenocarcinoma
by Ashleigh Hull, Yanrui Li, Dylan Bartholomeusz, William Hsieh, William Tieu, Tara L. Pukala, Alexander H. Staudacher and Eva Bezak
Cells 2022, 11(19), 2983; https://doi.org/10.3390/cells11192983 - 24 Sep 2022
Cited by 3 | Viewed by 2211
Abstract
Mucin 1 is a transmembrane glycoprotein which overexpresses cancer-specific epitopes (MUC1-CE) on pancreatic ductal adenocarcinoma (PDAC) cells. As PDAC is a low survival and highly aggressive malignancy, developing radioimmunoconjugates capable of targeting MUC1-CE could lead to improvements in PDAC outcomes. The aim of [...] Read more.
Mucin 1 is a transmembrane glycoprotein which overexpresses cancer-specific epitopes (MUC1-CE) on pancreatic ductal adenocarcinoma (PDAC) cells. As PDAC is a low survival and highly aggressive malignancy, developing radioimmunoconjugates capable of targeting MUC1-CE could lead to improvements in PDAC outcomes. The aim of this study was to develop and perform preliminary testing of diagnostic and therapeutic radioimmunoconjugates for PDAC using an anti-MUC1 antibody, C595. Firstly, p-SCN-Bn-DOTA was conjugated to the C595 antibody to form a DOTA-C595 immunoconjugate. The stability and binding affinity of the DOTA-C595 conjugate was evaluated using mass spectrometry and ELISA. DOTA-C595 was radiolabelled to Copper-64, Lutetium-177, Gallium-68 and Technetium-99m to form novel radioimmunoconjugates. Cell binding assays were performed in PANC-1 (strong MUC1-CE expression) and AsPC-1 (weak MUC1-CE expression) cell lines using 64Cu-DOTA-C595 and 177Lu-DOTA-C595. An optimal molar ratio of 4:1 DOTA groups per C595 molecule was obtained from the conjugation process. DOTA-C595 labelled to Copper-64, Lutetium-177, and Technetium-99m with high efficiency, although the Gallium-68 labelling was low. 177Lu-DOTA-C595 demonstrated high cellular binding to the PANC-1 cell lines which was significantly greater than AsPC-1 binding at concentrations exceeding 100 nM (p < 0.05). 64Cu-DOTA-C595 showed similar binding to the PANC-1 and AsPC-1 cells with no significant differences observed between cell lines (p > 0.05). The high cellular binding of 177Lu-DOTA-C595 to MUC1-CE positive cell lines suggests promise as a therapeutic radioimmunoconjugate against PDAC while further work is required to harness the potential of 64Cu-DOTA-C595 as a diagnostic radioimmunoconjugate. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Molecular Mechanisms to Therapeutic Opportunities)
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Review

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16 pages, 674 KiB  
Review
Cell Dissemination in Pancreatic Cancer
by Jungsun Kim
Cells 2022, 11(22), 3683; https://doi.org/10.3390/cells11223683 - 19 Nov 2022
Cited by 8 | Viewed by 3267
Abstract
Pancreatic cancer is a disease notorious for its high frequency of recurrence and low survival rate. Surgery is the most effective treatment for localized pancreatic cancer, but most cancer recurs after surgery, and patients die within ten years of diagnosis. The question persists: [...] Read more.
Pancreatic cancer is a disease notorious for its high frequency of recurrence and low survival rate. Surgery is the most effective treatment for localized pancreatic cancer, but most cancer recurs after surgery, and patients die within ten years of diagnosis. The question persists: what makes pancreatic cancer recur and metastasize with such a high frequency? Herein, we review evidence that subclinical dormant pancreatic cancer cells disseminate before developing metastatic or recurring cancer. We then discuss several routes by which pancreatic cancer migrates and the mechanisms by which pancreatic cancer cells adapt. Lastly, we discuss unanswered questions in pancreatic cancer cell migration and our perspectives. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Molecular Mechanisms to Therapeutic Opportunities)
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25 pages, 42001 KiB  
Review
Enhancing an Oxidative “Trojan Horse” Action of Vitamin C with Arsenic Trioxide for Effective Suppression of KRAS-Mutant Cancers: A Promising Path at the Bedside
by Agata N. Burska, Bayansulu Ilyassova, Aruzhan Dildabek, Medina Khamijan, Dinara Begimbetova, Ferdinand Molnár and Dos D. Sarbassov
Cells 2022, 11(21), 3454; https://doi.org/10.3390/cells11213454 - 1 Nov 2022
Cited by 4 | Viewed by 2837
Abstract
The turn-on mutations of the KRAS gene, coding a small GTPase coupling growth factor signaling, are contributing to nearly 25% of all human cancers, leading to highly malignant tumors with poor outcomes. Targeting of oncogenic KRAS remains a most challenging task in oncology. [...] Read more.
The turn-on mutations of the KRAS gene, coding a small GTPase coupling growth factor signaling, are contributing to nearly 25% of all human cancers, leading to highly malignant tumors with poor outcomes. Targeting of oncogenic KRAS remains a most challenging task in oncology. Recently, the specific G12C mutant KRAS inhibitors have been developed but with a limited clinical outcome because they acquire drug resistance. Alternatively, exploiting a metabolic breach of KRAS-mutant cancer cells related to a glucose-dependent sensitivity to oxidative stress is becoming a promising indirect cancer targeting approach. Here, we discuss the use of a vitamin C (VC) acting in high dose as an oxidative “Trojan horse” agent for KRAS-mutant cancer cells that can be potentiated with another oxidizing drug arsenic trioxide (ATO) to obtain a potent and selective cytotoxic impact. Moreover, we outline the advantages of VC’s non-natural enantiomer, D-VC, because of its distinctive pharmacokinetics and lower toxicity. Thus, the D-VC and ATO combination shows a promising path to treat KRAS-mutant cancers in clinical settings. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Molecular Mechanisms to Therapeutic Opportunities)
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18 pages, 4012 KiB  
Review
Pancreatic Ductal Adenocarcinoma: Molecular Pathology and Predictive Biomarkers
by Mehran Taherian, Hua Wang and Huamin Wang
Cells 2022, 11(19), 3068; https://doi.org/10.3390/cells11193068 - 29 Sep 2022
Cited by 16 | Viewed by 6881
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis due to the lack of methods or biomarkers for early diagnosis and its resistance to conventional treatment modalities, targeted therapies, and immunotherapies. PDACs are a heterogenous group of malignant epithelial neoplasms with various histomorphological [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis due to the lack of methods or biomarkers for early diagnosis and its resistance to conventional treatment modalities, targeted therapies, and immunotherapies. PDACs are a heterogenous group of malignant epithelial neoplasms with various histomorphological patterns and complex, heterogenous genetic/molecular landscapes. The newly proposed molecular classifications of PDAC based on extensive genomic, transcriptomic, proteomic and epigenetic data have provided significant insights into the molecular heterogeneity and aggressive biology of this deadly disease. Recent studies characterizing the tumor microenvironment (TME) have shed light on the dynamic interplays between the tumor cells and the immunosuppressive TME of PDAC, which is essential to disease progression, as well as its resistance to chemotherapy, newly developed targeted therapy and immunotherapy. There is a critical need for the development of predictive markers that can be clinically utilized to select effective personalized therapies for PDAC patients. In this review, we provide an overview of the histological and molecular heterogeneity and subtypes of PDAC, as well as its precursor lesions, immunosuppressive TME, and currently available predictive molecular markers for patients. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Molecular Mechanisms to Therapeutic Opportunities)
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22 pages, 1350 KiB  
Review
Role of the Tumor Microenvironment in Regulating Pancreatic Cancer Therapy Resistance
by Daiyong Deng, Riya Patel, Cheng-Yao Chiang and Pingping Hou
Cells 2022, 11(19), 2952; https://doi.org/10.3390/cells11192952 - 21 Sep 2022
Cited by 25 | Viewed by 4631
Abstract
Pancreatic cancer has a notoriously poor prognosis, exhibits persistent drug resistance, and lacks a cure. Unique features of the pancreatic tumor microenvironment exacerbate tumorigenesis, metastasis, and therapy resistance. Recent studies emphasize the importance of exploiting cells in the tumor microenvironment to thwart cancers. [...] Read more.
Pancreatic cancer has a notoriously poor prognosis, exhibits persistent drug resistance, and lacks a cure. Unique features of the pancreatic tumor microenvironment exacerbate tumorigenesis, metastasis, and therapy resistance. Recent studies emphasize the importance of exploiting cells in the tumor microenvironment to thwart cancers. In this review, we summarize the hallmarks of the multifaceted pancreatic tumor microenvironment, notably pancreatic stellate cells, tumor-associated fibroblasts, macrophages, and neutrophils, in the regulation of chemo-, radio-, immuno-, and targeted therapy resistance in pancreatic cancer. The molecular insight will facilitate the development of novel therapeutics against pancreatic cancer. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Molecular Mechanisms to Therapeutic Opportunities)
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