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Novel Biomarkers in Pancreatic Cancer

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

Deadline for manuscript submissions: closed (1 October 2023) | Viewed by 11742

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Dr. Damiano Caputo

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Associate Professor of Surgery, Head of the Laparoscopic and Mini-Invasive Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Università Campus Bio-Medico di Roma, Rome, Italy
Interests: pancreatic cancer; pancreatic surgery; hepatobiliary disease; liver surgery; mini invasive surgery, surgical oncology
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Dr. Daniela Pozzi

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Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy
Interests: drug delivery; gene delivery; lipofection; lipid membranes; early cancer detection; magnetic levitation
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Dr. Alessandro Coppola

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General Surgery Unit, Surgery Center, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
Interests: hepatobiliary-pancreatic surgery and cancers; abdominal surgical oncology; liver and pancreatic benign and chronic diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The identification of novel biomarkers is an urgent priority in pancreatic cancer management. From diagnosis to follow up and through to assessing responses to neoadjuvant and adjuvant treatments (e.g., radiotherapy, chemotherapy) and surgical resection, the availability of novel biomarkers could play a crucial role in the fight against this lethal disease.

The aim of this Special Issue is to collect the most relevant and recent findings in the field of the identification and development of novel biomarkers for pancreatic cancer. Furthermore, attention will be paid to contributions that highlight the potential role that novel biomarkers may have in guiding therapeutic decisions in the treatment of pancreatic cancer.

Research articles reflecting the fields of “in vitro” diagnostics and prognostics are welcome, as well as clinically applicable high-throughput diagnostic technologies that can provide oncologists with innovative companion diagnostics.

Dr. Damiano Caputo
Dr. Daniela Pozzi
Dr. Alessandro Coppola
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. 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

pancreatic cancer
biomarkers
treatment response
cancer prognosis
early diagnosis
cancer treatment
pancreatic surgery
chemotherapy
radiotherapy
technology

Published Papers (9 papers)

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Editorial

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4 pages, 156 KiB

Open AccessEditorial

Novel Biomarkers in Pancreatic Cancer

by Alessandro Coppola, Daniela Pozzi and Damiano Caputo

Cancers 2024, 16(3), 628; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16030628 - 31 Jan 2024

Viewed by 712

Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents a neoplasm with an increasing incidence in both sexes [...] Full article

(This article belongs to the Special Issue Novel Biomarkers in Pancreatic Cancer)

Research

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14 pages, 3060 KiB

Open AccessArticle

Digging into the NGS Information from a Large-Scale South European Population with Metastatic/Unresectable Pancreatic Ductal Adenocarcinoma: A Real-World Genomic Depiction

by Dimitrios C. Ziogas, Eirini Papadopoulou, Helen Gogas, Stratigoula Sakellariou, Evangellos Felekouras, Charalampos Theocharopoulos, Dimitra T. Stefanou, Maria Theochari, Ioannis Boukovinas, Dimitris Matthaios, Anna Koumarianou, Eleni Zairi, Michalis Liontos, Konstantinos Koutsoukos, Vasiliki Metaxa-Mariatou, George Kapetsis, Angeliki Meintani, Georgios N. Tsaousis and George Nasioulas

Cancers 2024, 16(1), 2; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16010002 - 19 Dec 2023

Viewed by 1073

Abstract

Despite ongoing oncological advances, pancreatic ductal adenocarcinoma (PDAC) continues to have an extremely poor prognosis with limited targeted and immunotherapeutic options. Its genomic background has not been fully characterized yet in large-scale populations all over the world. Methods: Replicating a recent study from China, we collected tissue samples from consecutive Greek patients with pathologically-confirmed metastatic/unresectable PDAC and retrospectively investigated their genomic landscape using next generation sequencing (NGS). Findings: From a cohort of 409 patients, NGS analysis was successfully achieved in 400 cases (56.50% males, median age: 61.8 years). Consistent with a previous study, KRAS was the most frequently mutated gene in 81.50% of tested samples, followed by TP53 (50.75%), CDKN2 (8%), and SMAD4 (7.50%). BRCA1/2 variants with on-label indications were detected in 2%, and 87.50% carried a variant associated with off-label treatment (KRAS, ERBB2, STK11, or HRR-genes), while 3.5% of the alterations had unknown/preliminary-studied actionability (TP53/CDKN2A). Most of HRR-alterations were in intermediate- and low-risk genes (CHEK2, RAD50, RAD51, ATM, FANCA, FANCL, FANCC, BAP1), with controversial actionability: 8% harbored a somatic non-BRCA1/2 alteration, 6 cases had a high-risk alteration (PALB2, RAD51C), and one co-presented a PALB2/BRCA2 alteration. Elevated LOH was associated with HRR-mutated status and TP53 mutations while lowered LOH was associated with KRAS alterations. Including TMB/MSI data, the potential benefit from an NGS-oriented treatment was increased from 1.91% to 13.74% (high-MSI: 0.3%, TMB > 10 muts/MB: 12.78%). TMB was slightly increased in females (4.75 vs. 4.46 muts/MB) and in individuals with age > 60 (4.77 vs. 4.40 muts/MB). About 28.41% showed PD-L1 > 1% either in tumor or immune cells, 15.75% expressed PD-L1 ≥ 10%, and only 1.18% had PD-L1 ≥ 50%. This is the largest depiction of real-world genomic characteristics of European patients with PDAC, which offers some useful clinical and research insights. Full article

(This article belongs to the Special Issue Novel Biomarkers in Pancreatic Cancer)

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11 pages, 1898 KiB

Open AccessArticle

Differential Expression and Diagnostic Value of MUC5AC Glycoforms in Pancreatic Ductal Adenocarcinoma

by Ashish Manne, Lianbo Yu, Phil A Hart, Allan Tsung and Ashwini Esnakula

Cancers 2023, 15(19), 4832; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15194832 - 02 Oct 2023

Viewed by 932

Abstract

We explored the differential expression and diagnostic value of two significant Mucin 5AC (MUC5AC) glycoforms, less-glycosylated immature (IM) and heavily-glycosylated mature (MM), in neoplastic diseases (NpD), including pancreatic ductal adenocarcinoma (PDA) and neuroendocrine tumors (NET), and non-neoplastic (non-NpD) diseases. Commercially available tissue microarray (TMA) was constructed from 96 patients, including 38 primary PDA (PT), 5 metastatic lesions (ML), 11 NET, and the rest being non-NpD tissues. Immunohistochemistry for MUC5AC was performed using CHL2 and 45M1 clones for IM and MM isoforms, respectively. MUC5AC (both glycoforms) are not detected in non-NpD. In MUC5AC-positive neoplastic tissues, IM was localized to the cytoplasm (Cy) while MM was identified in apical (Ap) and extracellular (Ec) regions too. One ML positive (omentum) in the TMA expressed both. For PDA vs. non-PDA, the sensitivity (SN) was higher with MM ± IM (71%) than MM (47%) or IM (65%)-alone. The specificity (SP) was 100% with MM-alone, which dropped with the addition of IM (96%) or IM-alone (93%). For NpD vs. non-NpD, the SN (MM + IM-59%, IM-55%, MM-37%) was inferior, and SP was 100% for both glycoforms (MM ± IM). The combination of MUC5AC glycoforms has high SP and reasonable SN to diagnose PDA. They have the potential to be a reliable diagnostic marker and should be investigated further in more extensive studies. Full article

(This article belongs to the Special Issue Novel Biomarkers in Pancreatic Cancer)

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22 pages, 3702 KiB

Open AccessArticle

Critical Role of Novel O-GlcNAcylation of S550 and S551 on the p65 Subunit of NF-κB in Pancreatic Cancer

by Aishat Motolani, Matthew Martin, Benlian Wang, Guanglong Jiang, Faranak Alipourgivi, Xiumei Huang, Ahmad Safa, Yunlong Liu and Tao Lu

Cancers 2023, 15(19), 4742; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15194742 - 27 Sep 2023

Viewed by 1379

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a mere 5-year survival of ~10%. This highlights the urgent need for innovative treatment options for PDAC patients. The nuclear factor κB (NF-κB) is a crucial transcription factor that is constitutively activated in PDAC. It mediates the transcription of oncogenic and inflammatory genes that facilitate multiple PDAC phenotypes. Thus, a better understanding of the mechanistic underpinnings of NF-κB activation holds great promise for PDAC diagnosis and effective therapeutics. Here, we report a novel finding that the p65 subunit of NF-κB is O-GlcNAcylated at serine 550 and 551 upon NF-κB activation. Importantly, the overexpression of either serine-to-alanine (S-A) single mutant (S550A or S551A) or double mutant (S550A/S551A) of p65 in PDAC cells impaired NF-κB nuclear translocation, p65 phosphorylation, and transcriptional activity, independent of IκBα degradation. Moreover, the p65 mutants downregulate a category of NF-κB-target genes, which play a role in perpetuating major cancer hallmarks. We further show that overexpression of the p65 mutants inhibited cellular proliferation, migration, and anchorage-independent growth of PDAC cells compared to WT-p65. Collectively, we discovered novel serine sites of p65 O-GlcNAcylation that drive NF-κB activation and PDAC phenotypes, thus opening new avenues by inhibiting the NF-κB O-GlcNAcylation enzyme, O-GlcNAc transferase (OGT), for PDAC treatment in the future. Full article

(This article belongs to the Special Issue Novel Biomarkers in Pancreatic Cancer)

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9 pages, 841 KiB

Open AccessArticle

Stratifying Risk for Pancreatic Cancer by Multiplexed Blood Test

by Luca Digiacomo, Erica Quagliarini, Daniela Pozzi, Roberto Coppola, Giulio Caracciolo and Damiano Caputo

Cancers 2023, 15(11), 2983; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15112983 - 30 May 2023

Cited by 2 | Viewed by 1061

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, for which mortality closely parallels incidence. So far, the available techniques for PDAC detection are either too invasive or not sensitive enough. To overcome this limitation, here we present a multiplexed point-of-care test that provides a “risk score” for each subject under investigation, by combining systemic inflammatory response biomarkers, standard laboratory tests, and the most recent nanoparticle-enabled blood (NEB) tests. The former parameters are routinely evaluated in clinical practice, whereas NEB tests have been recently proven as promising tools to assist in PDAC diagnosis. Our results revealed that PDAC patients and healthy subjects can be distinguished accurately (i.e., 88.9% specificity, 93.6% sensitivity) by the presented multiplexed point-of-care test, in a quick, non-invasive, and highly cost-efficient way. Furthermore, the test allows for the definition of a “risk threshold”, which can help clinicians to trace the optimal diagnostic and therapeutic care pathway for each patient. For these reasons, we envision that this work may accelerate progress in the early detection of PDAC and contribute to the design of screening programs for high-risk populations. Full article

(This article belongs to the Special Issue Novel Biomarkers in Pancreatic Cancer)

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13 pages, 1867 KiB

Open AccessArticle

Circulating Monocytes Serve as Novel Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma Patients

by Frederik J. Hansen, Paul David, Marina Akram, Samuel Knoedler, Anke Mittelstädt, Susanne Merkel, Malgorzata J. Podolska, Izabela Swierzy, Lotta Roßdeutsch, Bettina Klösch, Dina Kouhestani, Anna Anthuber, Alan Bénard, Maximilian Brunner, Christian Krautz, Robert Grützmann and Georg F. Weber

Cancers 2023, 15(2), 363; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15020363 - 05 Jan 2023

Cited by 3 | Viewed by 1825

Abstract

Pancreatic ductal adenocarcinoma (PDAC) ranks among the most fatal cancer diseases, widely accepted to have the most dismal prognoses. Although immunotherapy has broadly revolutionized cancer treatment, its value in PDAC appears to be relatively low. Exhibiting protumoral effects, monocytes have recently been proposed as potential targets of such immunotherapeutic regimens. However, to date, the body of evidence on monocytes’ role in PDAC is scarce. Therefore, we analyzed monocytes in the peripheral blood of 58 PDAC patients prior to surgery and compared them to healthy individuals. PDAC patients showed increased levels of monocytes when compared to healthy controls In addition, patients with perineural infiltration demonstrated a higher percentage of monocytes compared to non-infiltrating tumors and PDAC G3 was associated with higher monocyte levels than PDAC G2. Patients with monocyte levels > 5% were found to have an 8.9-fold increased risk for a G3 and perineural infiltrated PDAC resulting in poorer survival compared to patients with <5% monocyte levels. Furthermore, PDAC patients showed increased expressions of CD86 and CD11c and decreased expressions of PD-L1 on monocytes compared to healthy individuals. Finally, levels of monocytes correlated positively with concentrations of IL-6 and TNF-α in plasma of PDAC patients. Based on our findings, we propose monocytes as a novel prognostic biomarker. Large-scale studies are needed to further decipher the role of monocytes in PDAC and investigate their potential as therapeutic targets. Full article

(This article belongs to the Special Issue Novel Biomarkers in Pancreatic Cancer)

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12 pages, 1786 KiB

Open AccessArticle

Multiplexed Detection of Pancreatic Cancer by Combining a Nanoparticle-Enabled Blood Test and Plasma Levels of Acute-Phase Proteins

by Damiano Caputo, Alessandro Coppola, Erica Quagliarini, Riccardo Di Santo, Anna Laura Capriotti, Roberto Cammarata, Aldo Laganà, Massimiliano Papi, Luca Digiacomo, Roberto Coppola, Daniela Pozzi and Giulio Caracciolo

Cancers 2022, 14(19), 4658; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194658 - 25 Sep 2022

Cited by 7 | Viewed by 1842

Abstract

The development of new tools for the early detection of pancreatic ductal adenocarcinoma (PDAC) represents an area of intense research. Recently, the concept has emerged that multiplexed detection of different signatures from a single biospecimen (e.g., saliva, blood, etc.) may exhibit better diagnostic capability than single biomarkers. In this work, we develop a multiplexed strategy for detecting PDAC by combining characterization of the nanoparticle (NP)-protein corona, i.e., the protein layer that surrounds NPs upon exposure to biological fluids and circulating levels of plasma proteins belonging to the acute phase protein (APPs) family. As a first step, we developed a nanoparticle-enabled blood (NEB) test that employed 600 nm graphene oxide (GO) nanosheets and human plasma (HP) (5% vol/vol) to produce 75 personalized protein coronas (25 from healthy subjects and 50 from PDAC patients). Isolation and characterization of protein corona patterns by 1-dimensional (1D) SDS-PAGE identified significant differences in the abundance of low-molecular-weight corona proteins (20–30 kDa) between healthy subjects and PDAC patients. Coupling the outcomes of the NEB test with the circulating levels of alpha 2 globulins, we detected PDAC with a global capacity of 83.3%. Notably, a version of the multiplexed detection strategy run on sex-disaggregated data provided substantially better classification accuracy for men (93.1% vs. 77.8%). Nanoliquid chromatography tandem mass spectrometry (nano-LC MS/MS) experiments allowed to correlate PDAC with an altered enrichment of Apolipoprotein A-I, Apolipoprotein D, Complement factor D, Alpha-1-antichymotrypsin and Alpha-1-antitrypsin in the personalized protein corona. Moreover, other significant changes in the protein corona of PDAC patients were found. Overall, the developed multiplexed strategy is a valid tool for PDAC detection and paves the way for the identification of new potential PDAC biomarkers. Full article

(This article belongs to the Special Issue Novel Biomarkers in Pancreatic Cancer)

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Review

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12 pages, 945 KiB

Open AccessReview

Endoscopic Ultrasound-Guided Needle-Based Confocal Endomicroscopy as a Diagnostic Imaging Biomarker for Intraductal Papillary Mucinous Neoplasms

by Shreyas Krishna, Ahmed Abdelbaki, Phil A. Hart and Jorge D. Machicado

Cancers 2024, 16(6), 1238; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16061238 - 21 Mar 2024

Viewed by 653

Abstract

Pancreatic cancer is on track to become the second leading cause of cancer-related deaths by 2030, yet there is a lack of accurate diagnostic tests for early detection. Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer and are increasingly being detected. Despite the development and refinement of multiple guidelines, diagnosing high-grade dysplasia or cancer in IPMNs using clinical, radiologic, endosonographic, and cyst fluid features still falls short in terms of accuracy, leading to both under- and overtreatment. EUS-guided needle-based confocal laser endomicroscopy (nCLE) is a novel technology that allows real-time optical biopsies of pancreatic cystic lesions. Emerging data has demonstrated that EUS-nCLE can diagnose and risk stratify IPMNs more accurately than conventional diagnostic tools. Implementing EUS-nCLE in clinical practice can potentially improve early diagnosis of pancreatic cancer, reduce unnecessary surgeries of IPMNs with low-grade dysplasia, and advance the field of digital pathomics. In this review, we summarize the current evidence that supports using EUS-nCLE as a diagnostic imaging biomarker for diagnosing IPMNs and for risk stratifying their degree of neoplasia. Moreover, we will present emerging data on the role of adding artificial intelligence (AI) algorithms to nCLE and integrating novel fluid biomarkers into nCLE. Full article

(This article belongs to the Special Issue Novel Biomarkers in Pancreatic Cancer)

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15 pages, 929 KiB

Open AccessReview

Diagnostic Bioliquid Markers for Pancreatic Cancer: What We Have vs. What We Need

by Geou-Yarh Liou and Crystal J. Byrd

Cancers 2023, 15(9), 2446; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15092446 - 25 Apr 2023

Cited by 2 | Viewed by 1591

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, currently has a dismal five-year survival rate of approximately 10% due to late diagnosis and a lack of efficient treatment options such as surgery. Furthermore, the majority of PDAC patients have surgically unresectable cancer, meaning cancer cells have either reached the surrounding blood vessels or metastasized to other organs distant from the pancreas area, resulting in low survival rates as compared to other types of cancers. In contrast, the five-year survival rate of surgically resectable PDAC patients is currently 44%. The late diagnosis of PDAC is a result of little or no symptoms in its early stage of development and a lack of specific biomarkers that may be utilized in routine examinations in the clinic. Although healthcare professionals understand the importance of early detection of PDAC, the research on the subject has lagged and no significant changes in the death toll of PDAC patients has been observed. This review is focused on understanding potential biomarkers that may increase the early diagnosis of PDAC patients at its surgically resectable stage. Here, we summarize the currently available biomarkers used in the clinic as well as those being developed with the hope of providing insight into the future of liquid biomarkers to be used in routine examinations for the early diagnosis of PDAC. Full article

(This article belongs to the Special Issue Novel Biomarkers in Pancreatic Cancer)

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