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Pancreatic Disease: From Molecular Basis to Novel Therapies

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

Deadline for manuscript submissions: closed (20 April 2024) | Viewed by 10904

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Dr. Agnieszka B. Bialkowska

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Department of Medicine, Renaissance School of Medicine at Stony Brook University, 101 Nicolls Road, Stony Brook, NY 11794, USA
Interests: transcription factors; Krüppel-like factor 4 (KLF4); Krüppel-Like Factor 5 (KLF5); intestinal biology; injury; inflammation; pancreatic neoplasia; pancreatic cancer
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Special Issue Information

Dear Colleagues,

The pancreas, with its exocrine and endocrine functions, sits at the intersection of the body’s digestive and endocrine systems. Pancreatic acinar and ductal cells act accordantly to synthesize, store, and release digestive enzymes into pancreatic ducts, which drain into the duodenum. Pancreatic endocrine glands, called islets of Langerhans, regulate blood sugar levels by secreting two hormones into the blood: insulin and glucagon. The physiology of the pancreas is very tightly controlled, and disruptions result in pancreatitis (acute and chronic), pancreatic cancer, and Diabetes Mellitus (type 1 and 2). Several known perturbations induce acute pancreatitis, including the overactivation of trypsinogen, increased inflammatory cell infiltration, and the destruction of secretory cells. Recently, mitochondrial, lysosomal, and autophagic dysfunction, as well as calcium overload and increased endoplasmic reticulum stress, have been identified as drivers of pancreatitis progression. Chronic injury is characterized by fibro-inflammatory pathophysiology leading to the destruction of the pancreatic parenchyma. It is caused by genetic and environmental factors that are exacerbated by alcohol, nicotine, nutritional, and metabolic factors, to name a few. It has been shown that obesity, smoking, chronic pancreatitis, bacterial infections, and diabetes are primary risk factors for pancreatic cancer development. Diabetes Mellitus is characterized by impaired sugar, protein, and fat metabolism resulting from insulin deficiency. Managing pancreatic diseases has yet to be very successful. Thus, novel interventions are required that can necessitate a better understanding of the mechanisms underlying the development of pancreatic pathologies. This Special Issue highlights recent progress in understanding the physiology and pathophysiology of the pancreas and therapeutic developments.

Dr. Agnieszka B. Bialkowska
Guest Editor

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Keywords

pancreatitis
acinar-to-ductal neoplasia
early pancreatic neoplasia
fibroinflammatory disease
pancreatic cancer
Diabetes Mellitus

Published Papers (9 papers)

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Research

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18 pages, 5958 KiB

Open AccessArticle

High-Fat Diets Fed during Pregnancy Cause Changes to Pancreatic Tissue DNA Methylation and Protein Expression in the Offspring: A Multi-Omics Approach

by Lindsey Eileen and Maria Peterson

Int. J. Mol. Sci. 2024, 25(13), 7317; https://doi.org/10.3390/ijms25137317 - 3 Jul 2024

Viewed by 666

Abstract

Maternal obesity, caused by diets rich in fats and sugars during pregnancy, can predispose offspring to metabolic diseases such as diabetes. We hypothesized that obesity during pregnancy leads to increased DNA methylation and reduced protein expression in factors regulating β-cell function and apoptosis. Female C57BL/6J mice were fed a high-fat diet (HFD; 42% fat content; n = 3) or a control diet (CON; 16% fat content; n = 3) for fourteen weeks before and during pregnancy. Offspring were euthanized at 8 weeks and pancreatic tissue was collected. Isolated DNA was analyzed using whole-genome bisulfite sequencing. Protein expression was quantified using LC–MS. No significant differences in body weight were observed between HFD and control pups (p = 0.10). Whole-genome bisulfite sequencing identified 91,703 and 88,415 differentially methylated regions (DMRs) in CON vs. HFD male and female offspring. A total of 34 and 4 proteins were determined to have changes in expression that correlated with changes in DNA methylation in CON vs. HFD males and females, respectively. The majority of these factors were grouped into the metabolic function category via pathway analyses. This study illustrates the complex relationship between epigenetics, diet, and sex-specific responses, therefore offering insights into potential therapeutic targets and areas for further research. Full article

(This article belongs to the Special Issue Pancreatic Disease: From Molecular Basis to Novel Therapies)

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17 pages, 2837 KiB

Open AccessArticle

Diagnostic and Prognostic Markers for Pancreatitis and Pancreatic Ductal Adenocarcinoma

by Havish S. Kantheti, Michael A. Hale, Shreoshi Pal Choudhuri, Huocong Huang, Xu-dong Wang, Yalda Zolghadri, Giulio Innamorati, Sai Prasada Rao Manikonda, Naviya Reddy, Sarthak Reddy, Rahul K. Kollipara, Valbona Lumani, Luc Girard, Yakov Bezrukov, Pavel Demenkov, Raymond J. MacDonald, Rolf A. Brekken, Yonghao Yu and Thomas M. Wilkie

Int. J. Mol. Sci. 2024, 25(12), 6619; https://doi.org/10.3390/ijms25126619 - 16 Jun 2024

Viewed by 902

Abstract

Diagnostic markers are desperately needed for the early detection of pancreatic ductal adenocarcinoma (PDA). We describe sets of markers expressed in temporal order in mouse models during pancreatitis, PDA initiation and progression. Cell type specificity and the differential expression of PDA markers were identified by screening single cell (sc) RNAseq from tumor samples of a mouse model for PDA (KIC) at early and late stages of PDA progression compared to that of a normal pancreas. Candidate genes were identified from three sources: (1) an unsupervised screening of the genes preferentially expressed in mouse PDA tumors; (2) signaling pathways that drive PDA, including the Ras pathway, calcium signaling, and known cancer genes, or genes encoding proteins that were identified by differential mass spectrometry (MS) of mouse tumors and conditioned media from human cancer cell lines; and (3) genes whose expression is associated with poor or better prognoses (PAAD, oncolnc.org). The developmental progression of PDA was detected in the temporal order of gene expression in the cancer cells of the KIC mice. The earliest diagnostic markers were expressed in epithelial cancer cells in early-stage, but not late-stage, PDA tumors. Other early markers were expressed in the epithelium of both early- and late-state PDA tumors. Markers that were expressed somewhat later were first elevated in the epithelial cancer cells of the late-stage tumors, then in both epithelial and mesenchymal cells, or only in mesenchymal cells. Stromal markers were differentially expressed in early- and/or late-stage PDA neoplasia in fibroblast and hematopoietic cells (lymphocytes and/or macrophages) or broadly expressed in cancer and many stromal cell types. Pancreatitis is a risk factor for PDA in humans. Mouse models of pancreatitis, including caerulein treatment and the acinar-specific homozygous deletion of differentiation transcription factors (dTFs), were screened for the early expression of all PDA markers identified in the KIC neoplasia. Prognostic markers associated with a more rapid decline were identified and showed differential and cell-type-specific expression in PDA, predominately in late-stage epithelial and/or mesenchymal cancer cells. Select markers were validated by immunohistochemistry in mouse and human samples of a normal pancreas and those with early- and late-stage PDA. In total, we present 2165 individual diagnostic and prognostic markers for disease progression to be tested in humans from pancreatitis to late-stage PDA. Full article

(This article belongs to the Special Issue Pancreatic Disease: From Molecular Basis to Novel Therapies)

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11 pages, 820 KiB

Open AccessCommunication

Mutation Analysis of Pancreatic Juice and Plasma for the Detection of Pancreatic Cancer

by Iris J. M. Levink, Maurice P. H. M. Jansen, Zakia Azmani, Wilfred van IJcken, Ronald van Marion, Maikel P. Peppelenbosch, Djuna L. Cahen, Gwenny M. Fuhler and Marco J. Bruno

Int. J. Mol. Sci. 2023, 24(17), 13116; https://doi.org/10.3390/ijms241713116 - 23 Aug 2023

Cited by 2 | Viewed by 1452

Abstract

Molecular profiling may enable earlier detection of pancreatic cancer (PC) in high-risk individuals undergoing surveillance and allow for personalization of treatment. We hypothesized that the detection rate of DNA mutations is higher in pancreatic juice (PJ) than in plasma due to its closer contact with the pancreatic ductal system, from which pancreatic cancer cells originate, and higher overall cell-free DNA (cfDNA) concentrations. In this study, we included patients with pathology-proven PC or intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia (HGD) from two prospective clinical trials (KRASPanc and PACYFIC) for whom both PJ and plasma were available. We performed next-generation sequencing on PJ, plasma, and tissue samples and described the presence (and concordance) of mutations in these biomaterials. This study included 26 patients (25 PC and 1 IPMN with HGD), of which 7 were women (27%), with a median age of 71 years (IQR 12) and a median BMI of 23 kg/m² (IQR 4). Ten patients with PC (40%) were (borderline) resectable at baseline. Tissue was available from six patients (resection n = 5, biopsy n = 1). A median volume of 2.9 mL plasma (IQR 1.0 mL) and 0.7 mL PJ (IQR 0.1 mL, p < 0.001) was used for DNA isolation. PJ had a higher median cfDNA concentration (2.6 ng/μL (IQR 4.2)) than plasma (0.29 ng/μL (IQR 0.40)). A total of 41 unique somatic mutations were detected: 24 mutations in plasma (2 KRAS, 15 TP53, 2 SMAD4, 3 CDKN2A 1 CTNNB1, and 1 PIK3CA), 19 in PJ (3 KRAS, 15 TP53, and 1 SMAD4), and 8 in tissue (2 KRAS, 2 CDKN2A, and 4 TP53). The mutation detection rate (and the concordance with tissue) did not differ between plasma and PJ. In conclusion, while the concentration of cfDNA was indeed higher in PJ than in plasma, the mutation detection rate was not different. A few cancer-associated genetic variants were detected in both biomaterials. Further research is needed to increase the detection rate and assess the performance and suitability of plasma and PJ for PC (early) detection. Full article

(This article belongs to the Special Issue Pancreatic Disease: From Molecular Basis to Novel Therapies)

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Review

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18 pages, 1764 KiB

Open AccessReview

CAFs-Associated Genes (CAFGs) in Pancreatic Ductal Adenocarcinoma (PDAC) and Novel Therapeutic Strategy

by Keishi Yamashita and Yusuke Kumamoto

Int. J. Mol. Sci. 2024, 25(11), 6003; https://doi.org/10.3390/ijms25116003 - 30 May 2024

Viewed by 924

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer with striking fibrosis, and its mortality rate is ranked second across human cancers. Cancer-associated fibroblasts (CAFs) play a critical role in PDAC progression, and we reviewed the molecular understanding of PDAC CAFs and novel therapeutic potential at present. CAFs-associated genes (CAFGs) were tentatively classified into three categories by stroma specificity representing stroma/epithelia expression ratios (SE ratios). The recent classification using single cell transcriptome technology clarified that CAFs were composed of myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and other minor ones (e.g., POSTN-CAFs and antigen presenting CAFs, apCAFs). LRRC15 is a myCAFs marker, and myCAFs depletion by diphtheria toxin induces the rapid accumulation of cytotoxic T lymphocytes (CTLs) and therefore augment PDL1 antibody treatments. This finding proposes that myCAFs may be a critical regulator of tumor immunity in terms of PDAC progression. myCAFs are located in CAFs adjacent to tumor cells, while iCAFs marked by PDPN and/or COL14A1 are distant from tumor cells, where hypoxic and acidic environments being located in iCAFs putatively due to poor blood supply is consistent with HIF1A and GPR68 expressions. iCAFs may be shared with SASP (secretion-associated phenotypes) in senescent CAFs. myCAFs are classically characterized by CAFGs induced by TGFB1, while chemoresistant CAFs with SASP may dependent on IL6 expression and accompanied by STAT3 activation. Recently, it was found that the unique metabolism of CAFs can be targeted to prevent PDAC progression, where PDAC cells utilize glucose, whereas CAFs in turn utilize lactate, which may be epigenetically regulated, mediated by its target genes including CXCR4. In summary, CAFs have unique molecular characteristics, which have been rigorously clarified as novel therapeutic targets of PDAC progression. Full article

(This article belongs to the Special Issue Pancreatic Disease: From Molecular Basis to Novel Therapies)

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16 pages, 731 KiB

Open AccessReview

The Pivotal Role of Macrophages in the Pathogenesis of Pancreatic Diseases

by Seungyeon Ryu and Eun Kyung Lee

Int. J. Mol. Sci. 2024, 25(11), 5765; https://doi.org/10.3390/ijms25115765 - 25 May 2024

Viewed by 807

Abstract

The pancreas is an organ with both exocrine and endocrine functions, comprising a highly organized and complex tissue microenvironment composed of diverse cellular and non-cellular components. The impairment of microenvironmental homeostasis, mediated by the dysregulation of cell-to-cell crosstalk, can lead to pancreatic diseases such as pancreatitis, diabetes, and pancreatic cancer. Macrophages, key immune effector cells, can dynamically modulate their polarization status between pro-inflammatory (M1) and anti-inflammatory (M2) modes, critically influencing the homeostasis of the pancreatic microenvironment and thus playing a pivotal role in the pathogenesis of the pancreatic disease. This review aims to summarize current findings and provide detailed mechanistic insights into how alterations mediated by macrophage polarization contribute to the pathogenesis of pancreatic disorders. By analyzing current research comprehensively, this article endeavors to deepen our mechanistic understanding of regulatory molecules that affect macrophage polarity and the intricate crosstalk that regulates pancreatic function within the microenvironment, thereby facilitating the development of innovative therapeutic strategies that target perturbations in the pancreatic microenvironment. Full article

(This article belongs to the Special Issue Pancreatic Disease: From Molecular Basis to Novel Therapies)

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20 pages, 1080 KiB

Open AccessReview

Unveiling the Molecular Landscape of Pancreatic Ductal Adenocarcinoma: Insights into the Role of the COMPASS-like Complex

by Marzieh Jamali, Erfaneh Barar and Jiaqi Shi

Int. J. Mol. Sci. 2024, 25(10), 5069; https://doi.org/10.3390/ijms25105069 - 7 May 2024

Viewed by 932

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is poised to become the second leading cause of cancer-related death by 2030, necessitating innovative therapeutic strategies. Genetic and epigenetic alterations, including those involving the COMPASS-like complex genes, have emerged as critical drivers of PDAC progression. This review explores the genetic and epigenetic landscape of PDAC, focusing on the role of the COMPASS-like complex in regulating chromatin accessibility and gene expression. Specifically, we delve into the functions of key components such as KDM6A, KMT2D, KMT2C, KMT2A, and KMT2B, highlighting their significance as potential therapeutic targets. Furthermore, we discuss the implications of these findings for developing novel treatment modalities for PDAC. Full article

(This article belongs to the Special Issue Pancreatic Disease: From Molecular Basis to Novel Therapies)

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31 pages, 4651 KiB

Open AccessReview

The Importance of Intra-Islet Communication in the Function and Plasticity of the Islets of Langerhans during Health and Diabetes

by Thomas G. Hill and David J. Hill

Int. J. Mol. Sci. 2024, 25(7), 4070; https://doi.org/10.3390/ijms25074070 - 6 Apr 2024

Viewed by 1432

Abstract

Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory stimuli. However, within individual islets, there is also multi-faceted coordination of function between individual beta-cells, and between beta-cells and other endocrine and vascular cell types. This is mediated partly through circulatory feedback of the major secreted hormones, insulin and glucagon, but also by autocrine and paracrine actions within the islet by a range of other secreted products, including somatostatin, urocortin 3, serotonin, glucagon-like peptide-1, acetylcholine, and ghrelin. Their availability can be modulated within the islet by pericyte-mediated regulation of microvascular blood flow. Within the islet, both endocrine progenitor cells and the ability of endocrine cells to trans-differentiate between phenotypes can alter endocrine cell mass to adapt to changed metabolic circumstances, regulated by the within-islet trophic environment. Optimal islet function is precariously balanced due to the high metabolic rate required by beta-cells to synthesize and secrete insulin, and they are susceptible to oxidative and endoplasmic reticular stress in the face of high metabolic demand. Resulting changes in paracrine dynamics within the islets can contribute to the emergence of Types 1, 2 and gestational diabetes. Full article

(This article belongs to the Special Issue Pancreatic Disease: From Molecular Basis to Novel Therapies)

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20 pages, 887 KiB

Open AccessReview

Functional and Potential Therapeutic Implication of MicroRNAs in Pancreatic Cancer

by Amartya Pal, Anushka Ojha and Jingfang Ju

Int. J. Mol. Sci. 2023, 24(24), 17523; https://doi.org/10.3390/ijms242417523 - 15 Dec 2023

Cited by 2 | Viewed by 1475

Abstract

The alarmingly low five-year survival rate for pancreatic cancer presents a global health challenge, contributing to about 7% of all cancer-related deaths. Late-stage diagnosis and high heterogeneity are the biggest hurdles in treating pancreatic cancer. Thus, there is a pressing need to discover novel biomarkers that could help in early detection as well as improve therapeutic strategies. MicroRNAs (miRNAs), a class of short non-coding RNA, have emerged as promising candidates with regard to both diagnostics and therapeutics. Dysregulated miRNAs play pivotal roles in accelerating tumor growth and metastasis, orchestrating tumor microenvironment, and conferring chemoresistance in pancreatic cancer. The differential expression profiles of miRNAs in pancreatic cancer could be utilized to explore novel therapeutic strategies. In this review, we also covered studies on recent advancements in various miRNA-based therapeutics such as restoring miRNAs with a tumor-suppressive function, suppressing miRNA with an oncogenic function, and combination with chemotherapeutic drugs. Despite several challenges in terms of specificity and targeted delivery, miRNA-based therapies hold the potential to revolutionize the treatment of pancreatic cancer by simultaneously targeting multiple signaling pathways. Full article

(This article belongs to the Special Issue Pancreatic Disease: From Molecular Basis to Novel Therapies)

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Other

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11 pages, 4237 KiB

Open AccessBrief Report

Undifferentiated Carcinoma with Osteoclast-like Giant Cells of the Pancreas: Molecular Genetic Analysis of 13 Cases

by Jan Hrudka, Markéta Kalinová, Vanda Ciprová, Jana Moravcová, Radim Dvořák and Radoslav Matěj

Int. J. Mol. Sci. 2024, 25(6), 3285; https://doi.org/10.3390/ijms25063285 - 14 Mar 2024

Cited by 2 | Viewed by 1149

Abstract

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas is a rare malignancy regarded as a subvariant of pancreatic ductal carcinoma (PDAC) characterized by variable prognosis. UCOGC shows a strikingly similar spectrum of oncogenic DNA mutations to PDAC. In the current work, we analyzed the landscape of somatic mutations in a set of 13 UCOGC cases via next-generation sequencing (NGS). We detected a spectrum of pathogenic or likely pathogenic mutations similar to those observed in PDAC following previously published results (10 KRAS, 9 TP53, 4 CDKN2A, and 1 SMAD4, CIC, GNAS, APC, ATM, NF1, FBXW7, ATR, and FGFR3). Our results support the theory that UCOGC is a variant of PDAC, despite its unique morphology; however, a UCOGC-specific genomic signature as well as predictive markers remain mainly unknown. Programmed death ligand 1 (PD-L1) status remains an important predictive marker based on previous studies. Full article

(This article belongs to the Special Issue Pancreatic Disease: From Molecular Basis to Novel Therapies)

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