Pancreatic cancer is the third leading cause of cancer-related deaths in the United States, owing to its aggressive nature and suboptimal treatment options, emphasizing the need for novel therapeutic approaches. Emerging studies have exhibited promising results regarding the therapeutic utility of plant-derived compounds (phytochemicals) in pancreatic cancer. The purpose of this review is to evaluate the potential of phytochemicals in the treatment and prevention of pancreatic cancer. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses was applied to collect articles for this review. Scholarly databases, including PubMed, Scopus and ScienceDirect, were queried for relevant studies using the following keywords: phytochemicals, phenolics, terpenoids, alkaloids, sulfur-containing compounds, in vitro, in vivo, clinical studies, pancreatic cancer, tumour, treatment and prevention. Aggregate results pooled from qualified studies indicate phytochemicals can inhibit pancreatic cancer cell growth or decrease tumour size and volume in animal models. These effects have been attributed to various mechanisms, such as increasing proapoptotic factors, decreasing antiapoptotic factors, or inducing cell death and cell cycle arrest. Notable signalling pathways modulated by phytochemicals include the rat sarcoma/mitogen activated protein kinase, wingless-related integration site/β-catenin and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signal transduction pathways. Clinically, phytochemicals have been found to increase survival while being well-tolerated and safe, though research is scarce. While these promising results have produced great interest in this field, further in-depth studies are required to characterize the anticancer activities of phytochemicals before they can be utilized to prevent or treat pancreatic cancer in clinical practice. LINKED ARTICLES: This article is part of a themed issue Natural Products and Cancer: From Drug Discovery to Prevention and Therapy. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.10/issuetoc.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited early diagnostic methods and therapeutic options, contributing to its poor prognosis. Recent advances in high-throughput sequencing have highlighted the critical roles of noncoding RNAs (ncRNAs), particularly PIWI-interacting RNAs (piRNAs), in cancer biology. In this review, we systematically summarize the emerging roles of piRNAs and their associated PIWI proteins in PDAC pathogenesis, progression, and prognosis. We provide a comprehensive analysis of the molecular mechanisms by which piRNAs/PIWIs regulate gene expression and cellular signaling pathways in PDAC. Furthermore, we discuss their potential as novel biomarkers for early diagnosis and therapeutic targets. Importantly, this review identifies key piRNAs/PIWIs involved in PDAC and proposes innovative strategies for improving diagnosis and treatment outcomes. Our work not only consolidates current knowledge but also offers new perspectives for future research and clinical applications in PDAC management.

Treating pancreatic ductal adenocarcinoma (PDAC) is a major clinical challenge, owing to its poor prognosis. Understanding the underlying molecular interactions may be crucial in determining PDAC intractability. We elucidated the combinatory role of SMAD family member 4 (SMAD4) and runt-related transcription factor 3 (RUNX3) in PDAC.

Formalin-fixed and paraffin-embedded tissues were obtained from 101 patients who underwent surgical resection of PDAC. SMAD4 and RUNX3 expression in the tissues was evaluated using immunohistochemistry. SMAD4 and KRAS mutations were evaluated using Sanger sequencing. SMAD4 copy number variations were evaluated using quantitative real-time polymerase chain reaction. These molecular characteristics were compared with patients' clinicopathological features.

Retained SMAD4 expression in PDAC tissues was associated with higher tumor, node, metastasis (TNM) stage, and metastatic recurrence. Defective RUNX3 expression was associated with higher TNM stages. Further analysis to determine significance of retained SMAD4 indicated that all these cases had defective RUNX3 expression; therefore, the combined expression status of retained SMAD4 and defective RUNX3 expression in tissues was determined to be associated with higher TNM stage and metastatic recurrence than defective SMAD4 expression with defective or retained RUNX3 expression. Survival analysis showed that patients with tumors with retained SMAD4 and defective RUNX3 expression had relatively worse overall survival rates. KRAS mutations were not associated with SMAD4/RUNX3 expression or overall survival.

Despite inherent limitations of this retrospective study and small sample size, our findings highlight the potential combined role of SMAD4 and RUNX3 in node metastasis and metastatic recurrence in patients with resected PDAC.

The regucalcin gene is located on the X chromosome, comprising seven exons and six introns. This gene and protein are expressed in various tissues and cells and is predominantly expressed in human liver, kidney, and adrenal tissues. Regucalcin gene expression is enhanced via a mechanism mediated by several signaling molecules and transcription factors. Regucalcin plays a multifunctional role in cellular regulation in maintaining cell homeostasis. In addition, regucalcin has been implicated in several metabolic disorders and diseases. In particular, regucalcin plays a role as a novel suppressor in several types of cancer patients. Increased expression of regucalcin suppresses the growth of human cancer cells, suggesting its pivotal role in suppressing tumor development. The survival time of cancer patients is prolonged with increased expression of regucalcin in the tumor tissues. The adhesion, migration, invasion, and bone metastatic activity of cancer cells are blocked by the overexpression of regucalcin, promoting dormancy in cancer patients. Interestingly, regucalcin is also found in human serum, suggesting its character as a novel biomarker in various diseases. This extracellular regucalcin has been shown to suppress human cancer cells' growth and bone metastatic activity. Thus, extracellular regucalcin may play a vital role as a suppressor of human cancer activity. Alteration of the serum regucalcin levels in physiological and pathophysiological conditions may influence the activity of cancer cells in the microenvironment. This review will discuss the potential role of extracellular regucalcin in cancer cell activity as a critical suppressor in the cancer microenvironment.

Pancreatic cancer kills millions of people worldwide each year and is one of the most prevalent causes of mortality that requires prompt therapy. A large number of people suffering from pancreatic cancer are detected at an advanced stage, with incurable and drug-resistant tumor, hence the overall survival rate of pancreatic cancer is less. The advance phase of this cancer is generated because of expression of the cancer-causing gene, inactivation of the tumorsuppressing gene, and deregulation of molecules in different cellular signalling pathways. The prompt diagnosis through the biomarkers significantly evades the progress and accelerates the survival rates. The overexpression of Mesothelin, Urokinase plasminogen activator, IGFR, Epidermal growth factor receptor, Plectin-1, Mucin-1 and Zinc transporter 4 were recognized in the diagnosis of pancreatic cancer. Nanotechnology has led to the development of nanocarriersbased formulations (lipid, polymer, inorganic, carbon based and advanced nanocarriers) which overcome the hurdles of conventional therapy, chemotherapy and radiotherapy which causes toxicity to adjacent healthy tissues. The biocompatibility, toxicity and large-scale manufacturing are the hurdles associated with the nanocarriers-based approaches. Currently, Immunotherapybased techniques emerged as an efficient therapeutic alternative for the prevention of cancer. Immunological checkpoint targeting techniques have demonstrated significant efficacy in human cancers. Recent advancements in checkpoint inhibitors, adoptive T cell therapies, and cancer vaccines have shown potential in overcoming the immune evasion mechanisms of pancreatic cancer cells. Combining these immunotherapeutic approaches with nanocarriers holds great promise in enhancing the antitumor response and improving patient survival.

Benign lesions, inflammation, cysts and pseudocysts, as well as neoplasms of the exocrine and endocrine parts of the pancreas can be easily identified using cytological methods. The sensitivity and specificity can be increased with the help of additional examination methods. The sensitivity of intraoperative rapid cytology reaches about 99%. In the literature, the sensitivity reaches an average of about 85% for biopsies. The method is easy to use, has very low complication rates (1%-2%) and is safe for the patient.

1290 cytological samples from pancreatic lesions were processed in the institute of pathology at Hannover Medical School (MHH), as cytological smears and stained with Giemsa and PAS stains as conventional methods. They were compared with the histological specimens that were processed at the same institute. Immunocytochemistry and molecularpathology have been processed only in selected cases. In general, it is routine in the university that the patients give their written consent to participate in clinical studies. The local ethics committee has stated that there is no need for approval due to the retrospective nature of the study.

In this work, we detected 20.077% malignant lesions, 63.333% benign findings and inflammation, 7.441% pseudocysts and cysts. About 9.147% samples were unrepresentative due to insufficient number of cells.

This work will highlight the importance of fine aspiration cytology (FNAC) of suspicious pancreatic lesions, its possibilities and limitations in routine diagnostics with discussing the differential diagnoses, pointing to its great value and safety for patients. FNAC is the gold standard, its power is strongly associated with high specificity and sensitivity in the diagnosis of pancreatic lesions, and is very useful in the differential diagnosis between malignant and inflammatory lesions in pancreas.

Pancreas is a vital gland of gastrointestinal system with exocrine and endocrine secretory functions, interweaved into essential metabolic circuitries of the human body. Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal malignancies, with a 5-year survival rate of 11%. This poor prognosis is primarily attributed to the absence of early symptoms, rapid metastatic dissemination, and the limited efficacy of current therapeutic interventions. Despite recent advancements in understanding the etiopathogenesis and treatment of PDAC, there remains a pressing need for improved individualized models, identification of novel molecular targets, and development of unbiased predictors of disease progression. Here we aim to explore the concept of precision medicine utilizing 3-dimensional, patient-specific cellular models of pancreatic tumors and discuss their potential applications in uncovering novel druggable molecular targets and predicting clinical parameters for individual patients.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with limited therapeutic options. Here, we evaluated the role of regulator of chromosome condensation 1 (RCC1) in PDAC. RCC1 functions as a guanine exchange factor for GTP-binding nuclear protein Ran (Ran) GTPase and is involved in nucleocytoplasmic transport. RCC1 RNA expression is elevated in PDAC tissues compared to normal pancreatic tissues and correlates with poor prognosis. RCC1 silencing by RNAi and CRISPR-Cas9 knockout (KO) results in reduced proliferation in 2-D and 3-D cell cultures. RCC1 knockdown (KD) reduced migration and clonogenicity, enhanced apoptosis, and altered cell cycle progression in human PDAC and murine cells from LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) tumors. Mechanistically, RCC1 KO shows widespread transcriptomic alterations including regulation of PTK7, a co-receptor of the Wnt signaling pathway. RCC1 KD disrupted subcellular Ran localization and the Ran gradient. Nuclear and cytosolic proteomics revealed altered subcellular proteome localization in Rcc1 KD KPC-tumor-derived cells and several altered metabolic biosynthesis pathways. In vivo, RCC1 KO cells show reduced tumor growth potential when injected as sub-cutaneous xenografts. Finally, RCC1 KD sensitized PDAC cells to gemcitabine chemotherapy treatment. This study reveals the role of RCC1 in pancreatic cancer as a novel molecular vulnerability that could be exploited to enhance therapeutic response.

Biological behaviour of Periampullary cancers (PACS) differs from pancreatic head cancer, and analysis of molecular alteration is needed. BRAF and HER2 are keys members of the RAS/RAF and EGFR pathway, playing roles in prognostic markers and therapeutic targets.

A study on 89 PACS patients, undergoing Whipple Pancreaticoduodenectomy, PCR-RFLP, and qPCR methods used for SNP and mRNA expression studies. Clinicopathological and survival data collected. Molecular changes were correlated with Clinicopathological parameters. Survival outcomes were assessed by Kaplan Meir Log rank test.

The study revealed that homozygous mutant BRAF V600E was significantly higher in PAC compared to a healthy control (p = 0.0012). Whereas the genotype frequency of HER2 I1655V was similar among PAC and healthy control. The A > G change in HER2 was associated with tumor arising from duodenum (p = 0.004) and showed poor survival outcome (p = 0.001). Upregulation of BRAF and HER2 was found in 43 % of patients with synergistic effect, the median overall survival (OS) being 50.5 ± 13 months. The increased expression of HER2 was higher in early stage (p = 0.04) PAC. The gene expression did not impact the OS, whereas female gender, G3 tumors, T3-T4 depth of tumour, advanced stage, LN metastasis, LVI and PNI were poor predictors of OS.

BRAF V600E SNP was associated with disease susceptibility, and had increased mRNA expression while HER2 I1655V SNP was associated with poor survival outcome in PAC. The increased expression of BRAF and HER2 in early tumors and their co-expression in PAC exhibit cross talk between RAS/RAF and EGFR pathway in PAC.

Cancer is the result of complex interactions of intrinsic and extrinsic cell processes, which promote sustained proliferation, resistance to apoptosis, reprogramming and reorganization. The evolution of any type of cancer emerges from the role of the microenvironmental conditions and their impact of some molecular complexes on certain signalling pathways. The understanding of the early onset of cancer requires a multiscale analysis of the cellular microenvironment. In this paper, we analyse a qualitative multiscale model of pancreatic adenocarcinoma by modelling the cellular microenvironment through elastic cell interactions and their intercellular communication mechanisms, such as growth factors and cytokines. We focus on the low-grade dysplasia (PanIN 1) and moderate dysplasia (PanIN 2) stages of pancreatic adenocarcinoma. To this end, we propose a gene-regulatory network associated with the processes of proliferation and apoptosis of pancreatic cells and its kinetics in terms of delayed differential equations to mimic cell development. Likewise, we couple the cell cycle with the spatial distribution of cells and the transport of growth factors to show that the adenocarcinoma evolution is triggered by inflammatory processes. We show that the oncogene RAS may be an important target for developing anti-inflammatory strategies that limit the emergence of more aggressive adenocarcinomas.

In this review, we introduce the concept of cell competition, which occurs between heterogeneous neighboring cell populations. Cells with higher relative fitness become "winners" that outcompete cells of lower relative fitness ("losers"). We discuss the idea of super-competitors, mutant cells that expand at the expense of wild-type cells. Work on adult stem cells (ASCs) has revealed principles of neutral competition, wherein ASCs can be stochastically lost and replaced, and of biased competition, in which a winning ASC with a competitive advantage replaces its neighbors. Germline stem cells (GSCs) are ASCs that are uniquely endowed with the ability to produce gametes and, therefore, impact the next generation. Mechanisms of GSC competition have been elucidated by studies in Drosophila gonads, tunicates, and the mammalian testis. Competition between ASCs is thought to underlie various forms of cancer, including spermatocytic tumors in the human testis. Paternal age effect (PAE) disorders are caused by de novo mutations in human GSCs that increase their competitive ability and make them more likely to be inherited, leading to skeletal and craniofacial abnormalities in offspring. Given its widespread effects on human health, it is important to study GSC competition to elucidate how cells can become winners or losers.

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

Synthetic lethality is a novel model for cancer therapy. To understand the function and mechanism of BEN domain-containing protein 4 (BEND4) in pancreatic cancer, eight cell lines and a total of 492 cases of pancreatic neoplasia samples were included in this study. Methylation-specific polymerase chain reaction, CRISPR/Cas9, immunoprecipitation assay, comet assay, and xenograft mouse model were used. BEND4 is a new member of the BEN domain family. The expression of BEND4 is regulated by promoter region methylation. It is methylated in 58.1% (176/303) of pancreatic ductal adenocarcinoma (PDAC), 33.3% (14/42) of intraductal papillary mucinous neoplasm, 31.0% (13/42) of pancreatic neuroendocrine tumor, 14.3% (3/21) of mucinous cystic neoplasm, 4.3% (2/47) of solid pseudopapillary neoplasm, and 2.7% (1/37) of serous cystic neoplasm. BEND4 methylation is significantly associated with late-onset PDAC (> 50 years, P < 0.01) and tumor differentiation (P < 0.0001), and methylation of BEND4 is an independent poor prognostic marker (P < 0.01) in PDAC. Furthermore, BEND4 plays tumor-suppressive roles in vitro and in vivo. Mechanistically, BEND4 involves non-homologous end joining signaling by interacting with Ku80 and promotes DNA damage repair. Loss of BEND4 increased the sensitivity of PDAC cells to ATM inhibitor. Collectively, the present study revealed an uncharacterized tumor suppressor BEND4 and indicated that methylation of BEND4 may serve as a potential synthetic lethal marker for ATM inhibitor in PDAC treatment.

To construct a prognostic model for pancreatic cancer based on glycolytic and hypoxic metabolic subtypes. To analyze the biological characteristics of these subtypes and explore potential therapeutic options.

We obtained mRNA, simple nucleotide variation (SNP), and clinical data for pancreatic cancer from The Cancer Genome Atlas (TCGA). Patients were classified into four metabolic subtypes. We focused on glycolysis and hypoxia subtypes. Single-sample gene set enrichment analysis (ssGSEA) assessed immune cell infiltration. We evaluated the effects of immunotherapy and chemotherapy on these subtypes. Cox regression and random survival forest algorithms were used to build a prognostic model. Validation was performed using data from the International Cancer Genome Consortium (ICGC) and ArrayExpress database.

We identified four subtypes. Kaplan-Meier survival analysis showed the glycolytic subtype had the longest survival, while the hypoxic subtype had the shortest. The glycolytic subtype exhibited higher immune cell infiltration. Immunotherapy and chemotherapy appeared more beneficial for the glycolytic subtype. KRAS mutations were more frequent in the hypoxic subtype. Our prognostic model indicated a worse prognosis for high-risk groups, validated by external data.

The glycolytic metabolic subtype of pancreatic cancer is associated with longer survival and better response to chemotherapy and immunotherapy compared to the hypoxic subtype.

Pancreatic cancer (PC) is a dangerous digestive tract tumor that is becoming increasingly common and fatal. The most common form of PC is pancreatic ductal adenocarcinoma (PDAC). Bile acids (BAs) are closely linked to the growth and progression of PC. They can change the intestinal flora, increasing intestinal permeability and allowing gut microbes to enter the bloodstream, leading to chronic inflammation. High dietary lipids can increase BA secretion into the duodenum and fecal BA levels. BAs can cause genetic mutations, mitochondrial dysfunction, abnormal activation of intracellular trypsin, cytoskeletal damage, activation of NF-κB, acute pancreatitis, cell injury, and cell necrosis. They can act on different types of pancreatic cells and receptors, altering Ca2+ and iron levels, and related signals. Elevated levels of Ca2+ and iron are associated with cell necrosis and ferroptosis. Bile reflux into the pancreatic ducts can speed up the kinetics of epithelial cells, promoting the development of pancreatic intraductal papillary carcinoma. BAs can cause the enormous secretion of Glucagon-like peptide-1 (GLP-1), leading to the proliferation of pancreatic β-cells. Using Glucagon-like peptide-1 receptor agonist (GLP-1RA) increases the risk of pancreatitis and PC. Therefore, our objective was to explore various studies and thoroughly examine the role of BAs in PC.

We aimed to assess the diagnostic utility of an immunohistochemical panel including calcium-binding protein P, p53, Ki-67, and SMAD family member 4 and K-ras mutation for diagnosing pancreatic solid lesion specimens obtained by endoscopic ultrasound-guided fine-needle biopsy and to confirm their usefulness in histologically inconclusive cases.

Immunohistochemistry and peptide nucleic acid-clamping polymerase chain reaction for K-ras mutation were performed on 96 endoscopic ultrasound-guided fine-needle biopsy specimens. The diagnostic efficacy of each marker and the combination of markers was calculated. The diagnostic performances of these markers were evaluated in 27 endoscopic ultrasound-guided fine-needle biopsy specimens with histologically inconclusive diagnoses. A classification tree was constructed.

K-ras mutation showed the highest accuracy and consistency. Positivity in more than two or three of the five markers showed high diagnostic accuracy (94.6 % and 93.6 %, respectively), and positivity for more than three markers showed the highest accuracy for inconclusive cases (92.0 %). A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 showed high diagnostic performance, with only two misclassifications in inconclusive cases.

K-ras mutation detection via peptide nucleic acid-clamping polymerase chain reaction is a stable and accurate method for distinguishing between pancreatic ductal adenocarcinoma and non-pancreatic ductal adenocarcinoma lesions. A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 helps increase the diagnostic accuracy of cases that are histologically difficult to diagnose.

It is commonly assumed that gastrointestinal cancer is the most common form of cancer across the globe and is the leading contributor to cancer-related death. The intricate mechanisms underlying the growth of GI cancers have been identified. It is worth mentioning that both non-coding RNAs (ncRNAs) and certain types of RNA, such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), can have considerable impact on the development of gastrointestinal (GI) cancers. As a tumour suppressor, in the group of short non-coding regulatory RNAs is miR-34a. miR-34a silences multiple proto-oncogenes at the post-transcriptional stage by targeting them, which inhibits all physiologically relevant cell proliferation pathways. However, it has been discovered that deregulation of miR-34a plays important roles in the growth of tumors and the development of cancer, including invasion, metastasis, and the tumor-associated epithelial-mesenchymal transition (EMT). Further understanding of miR-34a's molecular pathways in cancer is also necessary for the development of precise diagnoses and effective treatments. We outlined the most recent research on miR-34a functions in GI cancers in this review. Additionally, we emphasize the significance of exosomal miR-34 in gastrointestinal cancers.

Pancreatic ductal adenocarcinoma (PDAC) can originate from acinar-to-ductal metaplasia (ADM). Pancreatic acini harboring oncogenic Kras mutations are transdifferentiated to a duct-like phenotype that further progresses to become pancreatic intraepithelial neoplasia (PanIN) lesions, giving rise to PDAC. Although ADM formation is frequently observed in KrasG12D transgenic mouse models of PDAC, the exact mechanisms of how oncogenic KrasG12D regulates this process remain an enigma. Herein, we revealed a new downstream target of oncogenic Kras, cytokine CCL9, during ADM formation. Higher levels of CCL9 and its receptors, CCR1 and CCR3, were detected in ADM regions of the pancreas in p48cre:KrasG12D mice and human PDAC patients. Knockdown of CCL9 in KrasG12D-expressed pancreatic acini reduced KrasG12D-induced ADM in a 3D organoid culture system. Moreover, exogenously added recombinant CCL9 and overexpression of CCL9 in primary pancreatic acini induced pancreatic ADM. We also showed that, functioning as a downstream target of KrasG12D, CCL9 promoted pancreatic ADM through upregulation of the intracellular levels of reactive oxygen species (ROS) and metalloproteinases (MMPs), including MMP14, MMP3 and MMP2. Blockade of MMPs via its generic inhibitor GM6001 or knockdown of specific MMP such as MMP14 and MMP3 decreased CCL9-induced pancreatic ADM. In p48cre:KrasG12D transgenic mice, blockade of CCL9 through its specific neutralizing antibody attenuated pancreatic ADM structures and PanIN lesion formation. Furthermore, it also diminished infiltrating macrophages and expression of MMP14, MMP3 and MMP2 in the ADM areas. Altogether, our results provide novel mechanistic insight into how oncogenic Kras enhances pancreatic ADM through its new downstream target molecule, CCL9, to initiate PDAC.

Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.

Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX), also known as lysine (K)-specific demethylase 6A (KDM6A), functions as a tumor suppressor gene or oncogene depending on the tumor type and context. However, its tumor-suppressive mechanisms remain largely unknown. Here, we investigated the clinical significance and biological effects of UTX expression in pancreatic ductal adenocarcinoma (PDA) and determined the potential mechanisms of its dysregulation. UTX expression and its association with clinicopathologic characteristics of PDA patients were analyzed using immunohistochemistry. UTX mRNA and protein expression and their regulation in PDA cell lines were measured using quantitative polymerase chain reaction and Western blot analyses. The biological functions of UTX in PDA cell growth, migration, and invasion were determined using gain- and loss-of-function assays with both in vitro and in vivo animal models. UTX expression was reduced in human PDA cell lines and specimens. Low UTX expression was associated with poor differentiation and prognosis in PDA. Forced UTX expression inhibited PDA proliferation, migration, and invasion in vitro and PDA growth and metastasis in vivo, whereas knockdown of UTX expression did the opposite. Mechanistically, UTX expression was trans-activated by GATA6 activation. GATA6-mediated PDA progression could be blocked, at least partially, by silencing UTX expression. In conclusion, loss of GATA6-mediated UTX expression was evident in human PDA and restored UTX expression suppressed PDA growth and metastasis. Thus, UTX is a tumor suppressor in PDA and may serve as a prognostic biomarker and therapeutic target.

Digestive tract tumors are heterogeneous and involve the dysregulation of multiple signaling pathways. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway plays a notable role in the oncogenesis of digestive tract tumors. Typically activated by pro-inflammatory cytokines, it regulates important biological processes, such as cell growth, differentiation, apoptosis, immune responses, and inflammation. The aberrant activation of this pathway manifests in different forms, including mutations in JAKs, overexpression of cytokine receptors, and sustained STAT activation, and contributes to promoting the malignant characteristics of cancer cells, including uncontrolled proliferation, resistance to apoptosis, enhanced invasion and metastasis, angiogenesis, acquisition of stem-like properties, and drug resistance. Numerous studies have shown that aberrant activation of the JAK-STAT pathway is closely related to the development and progression of digestive tract tumors, contributing to tumor survival, angiogenesis, changes in the tumor microenvironment, and even immune escape processes. In addition, this signaling pathway also affects the sensitivity of digestive tract tumors to chemotherapy and targeted therapy. Therefore, it is crucial to comprehensively understand the oncogenic mechanisms underlying the JAK-STAT pathway in order to develop effective therapeutic strategies against digestive tract tumors. Currently, several JAK-STAT inhibitors are undergoing clinical and preclinical trials as potential treatments for various human diseases. However, further investigation is required to determine the role of this pathway, as well as the effectiveness and safety of its inhibitors, especially in the context of digestive tract tumors. In this review, we provide an overview of the structure, classic activation, and negative regulation of the JAK-STAT pathway. Furthermore, we discuss the pathogenic mechanisms of JAK-STAT signaling in different digestive tract tumors, with the aim of identifying potential novel therapeutic targets. Video Abstract.

Pancreas ductal adenocarcinoma (PDAC) is a frequently lethal malignancy that poses unique therapeutic challenges. The current mainstay of therapy for metastatic PDAC (mPDAC) is cytotoxic chemotherapy. NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, oxaliplatin) is an emerging standard of care in the metastatic setting. An evolving understanding of PDAC pathogenesis is driving a shift toward targeted therapy. Olaparib, a poly-ADP-ribose polymerase (PARP) inhibitor, has regulatory approval for maintenance therapy in BRCA-mutated mPDAC along with other targeted agents receiving disease-agnostic approvals including for PDAC with rare fusions and mismatch repair deficiency. Ongoing research continues to identify and evaluate an expanding array of targeted therapies for PDAC.

This review provides a brief overview of standard therapies for PDAC and an emphasis on current and emerging targeted therapies.

There is notable potential for targeted therapies for KRAS-mutated PDAC with opportunity for meaningful benefit for a sizable portion of patients with this disease. Further, emerging approaches are focused on novel immune, tumor microenvironment, and synthetic lethality strategies.

Pancreatic ductal adenocarcinoma (PDAC) has a rising incidence and is one of the most lethal human malignancies. Much is known regarding the biology and pathophysiology of PDAC, but translating this knowledge to the clinic to improve patient outcomes has been challenging. In this Review, we discuss advances and practice-changing trials for PDAC. We briefly review therapeutic failures as well as ongoing research to refine the standard of care, including novel biomarkers and clinical trial designs. In addition, we highlight contemporary areas of research, including poly(ADP-ribose) polymerase inhibitors, KRAS-targeted therapies and immunotherapies. Finally, we discuss the future of pancreatic cancer research and areas for improvement in the next decade.

To explore the potential use of CDK inhibitors in pancreatic ductal adenocarcinoma (PDAC) therapy, a series of novel 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives was designed, synthesised, and investigated for inhibition on both CDK kinase activity and cellular proliferation of pancreatic cancer. Most of new sulphonamide-containing derivatives demonstrated strong inhibitory activity on CDK9 and obvious anti-proliferative activity in cell culture. Moreover, two new compounds suppressed cell proliferation of multiple human pancreatic cancer cell lines. The most potent compound 2g inhibited cancer cell proliferation by blocking Rb phosphorylation and induced apoptosis via downregulation of CDK9 downstream proteins Mcl-1 and c-Myc in MIA PaCa-2 cells. CDK9 knockdown experiment suggests its anti-proliferative activity is mainly mediated by CDK9. Additionally, 2g displayed moderate tumour inhibition effect in AsPC-1 derived xenograft mice model. Altogether, this study provided a new start for further optimisation to develop potential CDK inhibitor candidates for PDAC treatment by alone or combination use.

A severe global health concern is the rising incidence and mortality rate of colorectal cancer (CRC). Chemotherapy, which is typically used to treat CRC, is known to have limited specificity and can have noticeable side effects. A paradigm shift in cancer treatment has been brought about by the development of targeted therapies, which has led to the appearance of pharmacological agents with improved efficacy and decreased toxicity. Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), and BRAF are among the molecular targets covered in this review that are used in targeted therapy for CRC. The current discussion also covers advancements in targeted therapeutic approaches, such as antibody-drug conjugates, immune checkpoint inhibitors, and chimeric antigen receptor (CAR) T-cell therapy. A review of the clinical trials and application of these particular therapies in treating CRC is also done. Despite the improvements in targeted therapy for CRC, problems such as drug resistance and patient selection remain to be solved. Despite this, targeted therapies have offered fresh possibilities for identifying and treating CRC, paving the way for the development of personalized medicine and extending the life expectancy and general well-being of CRC patients.

Regucalcin, a calcium-binding protein lacking the EF-hand motif, was initially discovered in 1978. Its name is indicative of its function in calcium signaling regulation. The rgn gene encodes for regucalcin and is situated on the X chromosome in both humans and vertebrates. Regucalcin regulates pivotal enzymes involved in signal transduction and has an inhibitory function, which includes protein kinases, protein phosphatases, cysteinyl protease, nitric oxide dynthetase, aminoacyl-transfer ribonucleic acid (tRNA) synthetase, and protein synthesis. This cytoplasmic protein is transported to the nucleus where it regulates deoxyribonucleic acid and RNA synthesis as well as gene expression. Overexpression of regucalcin inhibits proliferation in both normal and cancer cells in vitro, independent of apoptosis. During liver regeneration in vivo, endogenous regucalcin suppresses cell growth when overexpressed. Regucalcin mRNA and protein expressions are significantly downregulated in tumor tissues of patients with various types of cancers. Patients exhibiting upregulated regucalcin in tumor tissue have shown prolonged survival. The decrease of regucalcin expression is linked to the advancement of cancer. Overexpression of regucalcin carries the potential for preventing and treating carcinogenesis. Additionally, extracellular regucalcin has displayed control over various types of human cancer cells. Regucalcin may hold a prominent role as a regulatory factor in cancer development. Supplying the regucalcin gene could prove to be a valuable asset in cancer treatment. The therapeutic value of regucalcin suggests its potential significance in treating cancer patients. This review delves into the most recent research on the regulatory role of regucalcin in human cancer development, providing a novel approach for treatment.

Meprins, zinc-dependent metalloproteinases belonging to the metzincin family, have been associated with various inflammatory diseases due to their abnormal expression and activity. In this study, we utilized pharmacophore modelling to identify crucial features for discovering potential dual inhibitors targeting meprins α and β. We screened four pharmacophoric features against a library of 270,540 natural compounds from the Zinc database, resulting in 84,092 matching compounds. Molecular docking was then performed on these compounds, targeting the active sites of meprins α and β. Docking results revealed six compounds capable of interacting with both isoforms, with binding affinities ranging from -10.0 to -10.5 kcal/mol and -6.9 to -9.9 kcal/mol for meprin α and β, respectively. Among these compounds, ZINC000008790788 and ZINC000095099469 displayed superior docking scores and MM-GBSA binding free energy compared to reference ligands. Furthermore, these two compounds exhibited acceptable predicted pharmacokinetic properties and stable interactions with meprins α and β during molecular dynamics simulations. This study presents a comprehensive approach for identifying potential dual inhibitors of meprin α and β, offering insights into the development of therapeutic interventions for inflammatory diseases associated with meprin dysregulation.

Despite recent advances, many cancers are still detected too late for curative treatment. There is, therefore, a need for the development of new diagnostic methods and biomarkers. One approach may arise from the detection of extrachromosomal circular DNA (eccDNA), which is part of cell-free DNA in human plasma.

First, we assessed and compared two methods for the purification of eccDNA from plasma. Second, we tested for an easy diagnostic application of eccDNA liquid biopsy-based assays.

For the comparison we tested a solid-phase silica purification method and a phenol/chloroform method with salt precipitation. For the diagnostic application of eccDNA we developed and tested a qPCR primer-based SNP detection system, for the detection of two well-established cancer-causing KRAS mutations (G12V and G12R) on circular DNA. This investigation was supported by purifying, sequencing, and analysing clinical plasma samples for eccDNAs containing KRAS mutant alleles in 0.5 mL plasma from 16 pancreatic ductal adenocarcinoma patients and 19 healthy controls.

In our method comparison we observed, that following exonuclease treatment a lower eccDNA yield was found for the phenol/chloroform method (15.7%-26.7%) compared with the solid-phase purification approach (47.8%-65.9%). For the diagnostic application of eccDNA tests, the sensitivity of the tested qPCR assay only reached ~10-3 in a background of 105 wild type (wt) KRAS circular entities, which was not improved by general amplification or primer-based inhibition of wt KRAS amplification. Furthermore, we did not detect eccDNA containing KRAS in any of the clinical samples.

A potential explanation for our inability to detect any KRAS mutations in the clinical samples may be related to the general low abundance of eccDNA in plasma.

Taken together our results provide a benchmark for eccDNA purification methods while raising the question of what is required for the optimal fast and sensitive detection of SNP mutations on eccDNA with greater sensitivity than primer-based qPCR detection.

Sotorasib is the first KRAS^G12C inhibitor approved by the US Food and Drug Administration for treating KRAS^G12C-mutant non-small-cell lung cancer (NSCLC). Clinical trials on the therapeutic use of sotorasib for cancer have reported promising results. However, KRAS^G12C-mutant cancers can acquire resistance to sotorasib after treatment. We incidentally discovered that sotorasib-resistant (SR) cancer cells are addicted to this inhibitor. In this study, we investigated the mechanisms underlying sotorasib addiction.

Sotorasib-resistant cells were established using KRAS^G12C-mutant pancreatic cancer and NSCLC cell lines. Cell viability in the presence or absence of sotorasib and in combination with multiple inhibitors was assessed through proliferation assay and annexin V/propidium iodide (PI) flow cytometry assays. The mechanisms underlying drug addiction were elucidated through 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, immunofluorescence staining, time-lapse microscopy, and comet assay. Furthermore, a subcutaneous xenograft model was used to demonstrate sotorasib addiction in vivo.

In the absence of sotorasib, the sotorasib-resistant cells underwent p21^Waf1/^Cip1-mediated cell cycle arrest and caspase-dependent apoptosis. Sotorasib withdrawal resulted in robust activation of mitogen-activated protein kinase (MAPK) pathway, inducing severe DNA damage and replication stress, which activated the DNA damage response (DDR) pathway. Persistent MAPK pathway hyperactivation with DDR exhaustion led to premature mitotic entry and aberrant mitosis, followed by micronucleus and nucleoplasmic bridge formation. Pharmacologic activation of the MAPK pathway with a type I BRAF inhibitor could further enhance the effects of sotorasib withdrawal on sotorasib-resistant cancer cells both in vitro and in vivo.

We elucidated the mechanisms underlying the sotorasib addiction of cancer cells. Sotorasib addiction appears to be mediated through MAPK pathway hyperactivity, DNA damage, replication stress, and mitotic catastrophe. Moreover, we devised a therapeutic strategy involving a type I BRAF inhibitor to strengthen the effects of sotorasib addiction; this strategy may provide clinical benefit for patients with cancer.

Pancreatic adenocarcinoma (PDAC) is one of the most common and lethal human cancers worldwide. Surgery followed by adjuvant chemotherapy offers the best chance of a long-term survival for patients with PDAC, although only approximately 20% of the patients have resectable tumors when diagnosed. Neoadjuvant chemotherapy (NACT) is recommended for borderline resectable pancreatic cancer. Several studies have investigated the role of NACT in treating resectable tumors based on the recent advances in PDAC biology, as NACT provides the potential benefit of selecting patients with favorable tumor biology and controls potential micro-metastases in high-risk patients with resectable PDAC. In such challenging cases, new potential tools, such as ct-DNA and molecular targeted therapy, are emerging as novel therapeutic options that may improve old paradigms. This review aims to summarize the current evidence regarding the role of NACT in treating non-metastatic pancreatic cancer while focusing on future perspectives in light of recent evidence.

Since the discovery of oncogenes in the 1970s, cancer doctors and researchers alike have understood the promise of discovering drugs to block the dominantly acting function of mutated signaling proteins in cancer. This promise was delivered, first slowly, with early signals inhibiting HER2 and BCR-Abl in the 1990s and 2000s, and then quickly, with kinase inhibitors being approved hand over fist in non-small cell lung cancer, melanoma, and many other malignancies. The RAS proteins, however, remained recalcitrant to chemical inhibition for decades, despite being, by far, the most frequently mutated oncogenes in cancers of all types. Nowhere was this deficit more palpable than in pancreatic ductal adenocarcinoma (PDA), where > 90% of cases are driven by single nucleotide substitutions at a single codon of the KRAS gene. The ice began to crack in 2012 when Ostrem and colleagues (Nature 503(7477): 548-551, 2013) synthesized the first KRAS G12C inhibitors, which covalently bind to GDP-bound G12C-mutated KRAS and lock the oncoprotein in its inactive state. In the last decade, the scientific community has established a new foundation on this and other druggable pockets in mutant KRAS. Here we provide an up-to-date overview of drugs targeting KRAS and other molecular targets in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is highly aggressive and has few treatment options. To personalize therapy, it is critical to delineate molecular subtypes and understand inter- and intra-tumoral heterogeneity. Germline testing for hereditary genetic abnormalities is recommended for all patients with PDA and somatic molecular testing is recommended for all patients with locally advanced or metastatic disease. KRAS mutations are present in 90% of PDA, while 10% are KRAS wild type and are potentially targetable with epidermal growth factor receptor blockade. KRASG12C inhibitors have shown activity in G12C-mutated cancers, and novel G12D and pan-RAS inhibitors are in clinical trials. DNA damage repair abnormalities, germline or somatic, occur in 5-10% of patients and are likely to benefit from DNA damaging agents and maintenance therapy with poly-ADP ribose polymerase inhibitors. Fewer than 1% of PDA harbor microsatellite instability high status and are susceptible to immune checkpoint blockade. Albeit very rare, occurring in <1% of patients with KRAS wild-type PDAs, BRAF V600E mutations, RET and NTRK fusions are targetable with cancer agnostic Food and Drug Administration-approved therapies. Genetic, epigenetic, and tumor microenvironment targets continue to be identified at an unprecedented pace, enabling PDA patients to be matched to targeted and immune therapeutics, including antibody-drug conjugates, and genetically engineered chimeric antigen receptor or T-cell receptor - T-cell therapies. In this review, we highlight clinically relevant molecular alterations and focus on targeted strategies that can improve patient outcomes through precision medicine.

Changes in the gut microbiome have been increasingly shown to accompany oncogenesis across various tumors. Similarly, microbial dysbiosis was found to be associated with pancreatic cancer progression and survival outcomes, expanding the field of tumor microenvironment research in pancreatic cancer. Mechanistic studies in pancreatic cancer models implicate components of the gut and pancreatic cancer microbiome in regulating tumorigenesis by altering cancer cell signaling, modulating immune function, and influencing the efficacy of current therapies in pancreatic cancer. This review discusses the outcomes of microbial modulation across various preclinical and clinical studies and highlights ongoing trials targeting the microbiome for pancreatic cancer therapy.

A family of inhibitors of cell differentiation or DNA-binding proteins, known as ID proteins (ID1-4), function as mighty transcription factors in various cellular processes, such as inhibiting differentiation, promoting cell-cycle progression, senescence, angiogenesis, tumorigenesis, and metastasis in cancer. Pancreatic cancer represents the deadliest cancer with the lowest survival rate of 10% due to the diagnosis at an advanced fatal stage and therapeutic resistance. Modestly, the only curative option for this lethal cancer is surgery but is done in less than 15-20% of patients because of the locally aggressive and early metastatic nature. Finding the earliest biomarkers and targeting the various hallmarks of pancreatic cancer can improve the treatment and survival of pancreatic cancer patients. Therefore, herein in this review, we explore in depth the potential roles of ID proteins function in hallmarks of pancreatic cancer, signaling pathways, and its oncogenic and tumor-suppressive effects. Hence, understanding the roles of dysregulated ID proteins would provide new insights into its function in pancreatic cancer tumorigenesis.

Colloid carcinoma (CC) is a rare subtype of pancreatic carcinoma. The aims of the study are to characterize the clinicopathological features and to evaluate the overall survival (OS) of patients with CC.

Patients diagnosed with pancreatic CC and pancreatic ductal adenocarcinoma (PDAC) between 2004 and 2016 were identified from the National Cancer Database using International Classification of Disease-O-3 morphology (8480/3 and 8140/3) and topography (C25) codes. Kaplan-Meier analysis and Cox proportional hazards models were used to analyze OS.

Fifty-six thousand eight hundred forty-six patients were identified. A total of 2430 patients (4.3%) were diagnosed with pancreatic CC. Males constituted 52.8% of CC and 52.2% of PDAC. Colloid carcinoma presented with pathological stage I disease more often (16.7% vs 5.9%) and stage IV disease less often (42.1% vs 52.4%) than PDAC (P < 0.001). Stage I CC received chemotherapy (36.0% vs 59.4%) and neoadjuvant chemotherapy (4.4% vs 14.2%) less often compared with PDAC (P < 0.001). Statistically significant improved OS was seen among stage I, II, and IV CC compared with PDAC.

Pancreatic CC presented as stage I disease more often compared with PDAC. Neoadjuvant chemotherapy was administered more often in stage I PDAC compared with CC. Colloid carcinoma had improved OS compared with PDAC among all stages except stage III.

Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF/cancer cell crosstalk could pave the way for new therapeutic strategies.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) cytology was one of the investigations for pancreatic masses. While the specificity approached 100%, its sensitivity remained low because of high rate of indeterminate and false-negative results. Meanwhile, KRAS gene was frequently mutated in up to 90% of pancreatic ductal adenocarcinoma and its precursor lesions. This study aimed to determine whether KRAS mutation analysis could improve the diagnostic sensitivity in EUS-FNA samples for pancreatic adenocarcinoma.

The EUS-FNA samples from patients with a pancreatic mass obtained between January 2016 and December 2017 were reviewed retrospectively. The cytology results were classified as malignant, suspicious for malignancy, atypical, negative for malignancy, and nondiagnostic. KRAS mutation testing was performed using polymerase chain reaction followed by Sanger sequencing.

A total of 126 EUS-FNA specimens were reviewed. The overall sensitivity and specificity by cytology alone were 29% and 100%, respectively. When KRAS mutation testing was performed in cases with indeterminate and negative cytology, the sensitivity increased to 74.2%, and the specificity remained at 100%.

KRAS mutation analysis, especially when performed in cytologically indeterminate cases, improves the diagnostic accuracy for pancreatic ductal adenocarcinoma. This may reduce the need to repeat invasive EUS-FNA for diagnosis.

The aims of this review were to determine whether positive peritoneal lavage cytology (CY+) precludes radical resection in pancreatic cancer and to propose prospections for future studies.

MEDLINE, Embase, and Cochrane Central were searched for related articles. Dichotomous variables and survival outcomes were analyzed with the estimation of odds ratio and hazards ratio (HR), respectively.

A total of 4905 patients were included, of which 7.8% were CY+. Positive peritoneal lavage cytology was correlated with poor overall survival (univariate survival analysis [HR, 2.35; P < 0.00001]; multivariate analysis [HR, 1.62; P < 0.00001]), poor recurrence-free survival (univariate survival analysis [HR, 2.50; P < 0.00001]; multivariate analysis [HR, 1.84; P < 0.00001]), and higher initial peritoneal recurrence rate (odds ratio, 5.49; P < 0.00001).

Although CY+ predicts poor prognosis and a higher risk of peritoneal metastasis after curative resection, it is not sufficient to preclude curative resection based on the current evidence, and high-quality trials should be conducted to assess the prognostic impact of operation among resectable CY+ patients. In addition, more sensitive and accurate methods to detect peritoneal exfoliated tumor cells and more effective comprehensive treatment for resectable CY+ pancreatic cancer patients are clearly warranted.

Pancreatic ductal adenocarcinoma (PDAC) develops via dysplastic changes in the epithelia graded as low- and high-grade with accumulation of molecular alterations. Constitutive activation of mitogen-activated protein kinase (MAPK) contributed by attenuation of DUSP6 plays a key role in sustaining PDAC. Active MAPK induces various molecules that function as effectors to sustain PDAC. AURKA and SON are downstream effectors that contribute substantially to the proliferation and survival of PDAC cells and are potentially useful as therapeutic targets. Active MAPK also promote microRNAs that modulate the proliferation of PDAC cells and are useful as diagnostic markers. Familial pancreatic cancer kindreds in Japan show various germline mutations supposed to increase a pancreatic cancer risk. Intraductal papillary mucinous neoplasms (IPMNs) consist of dilated ducts lined by papillary neoplastic epithelia of various shapes and varying grades of atypia. Various papillae of IPMNs are classified into four subtypes that are associated with clinicopathological features, including patient prognosis. GNAS is a specific driver gene for the development of IPMN through gain-of-function mutations. Tracing of molecular alterations has elucidated the mechanism of progression of IPMN from dysplasia to carcinoma, as well as one type of papillae. Intraductal tubulopapillary neoplasms belong to a distinct class of pancreatic neoplasms.

Gastric cancer is a major source of global cancer mortality with limited treatment options and poor patient survival. As our molecular understanding of gastric cancer improves, we are now beginning to recognize that these cancers are a heterogeneous group of diseases with incredibly unique pathogeneses and active oncogenic pathways. It is this molecular diversity and oftentimes lack of common oncogenic driver mutations that bestow the poor treatment responses that oncologists often face when treating gastric cancer. In this review, we will examine the treatments for gastric cancer including up-to-date molecularly targeted therapies and immunotherapies. We will then review the molecular subtypes of gastric cancer to highlight the diversity seen in this disease. We will then shift our discussion to basic science and gastric cancer mouse models as tools to study gastric cancer molecular heterogeneity. Furthermore, we will elaborate on a molecular process termed paligenosis and the cyclical hit model as key events during gastric cancer initiation that impart nondividing mature differentiated cells the ability to re-enter the cell cycle and accumulate disparate genomic mutations during years of chronic inflammation and injury. As our basic science understanding of gastric cancer advances, so too must our translational and clinical efforts. We will end with a discussion regarding single-cell molecular analyses and cancer organoid technologies as future translational avenues to advance our understanding of gastric cancer heterogeneity and to design precision-based gastric cancer treatments. Elucidation of interpatient and intratumor heterogeneity is the only way to advance future cancer prevention, diagnoses and treatment.

In both humans and cats, pancreatic carcinoma is an aggressive cancer with a grave prognosis. Proteomics techniques have successfully identified several blood-based biomarkers of human pancreatic neoplasia. Thus, this study aims to investigate whether similar biomarkers can be identified in the plasma of cats with FePAC by using liquid chromatography tandem mass spectrometry (LC-MS/MS). To facilitate evaluation of the low abundance plasma proteome, a human-based immunodepletion device (MARS-2) was first validated for use with feline plasma. Marked reduction and/or complete removal of albumin and immunoglobulins was confirmed by analysis of electrophoretograms and mass spectral data. Subsequently, plasma collected from 9 cats with pancreatic carcinoma (FePAC), 10 cats with symptomatic pancreatitis, and 10 healthy control cats was immunodepleted and subjected to LC-MS/MS. Thirty-seven plasma proteins were found to be differentially expressed (p < .05 in one-way ANOVA, FC >2 in fold change analysis). Among these proteins, ETS variant transcription factor 4 (p < .05) was overexpressed, while gelsolin (p < .01), tryptophan 2,3-dioxygenase (p < .05), serpin family F member 1 (p < .01), apolipoprotein A-IV (p < .01) and phosphatidylinositol-glycan-specific phospholipase D (p < .05) were down-regulated in cats with FePAC. Further studies on these potential biomarkers are needed to investigate their diagnostic value.

Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.

Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer related death. The urgent need for effective therapies is highlighted by the lack of adequate targeting. In PDAC, hedgehog (Hh) signaling is known to be aberrantly activated, which prompted the pathway as a possible target for effective treatment for PDAC patients. Unfortunately, specific targeting of upstream molecules within the Hh signaling pathway failed to bring clinical benefit. This led to the ongoing debate on Hh targeting as a therapeutic treatment for PDAC patients. Additionally, concurrent non-canonical activation routes also result in translocation of Gli transcription factors into the nucleus. Therefore, different downstream targets of the Hh signaling pathway were identified and evaluated in preclinical and clinical research. In this review we summarize the variety of Hh signaling antagonists in different preclinical models of PDAC. Furthermore, we discuss published and ongoing clinical trials that evaluated Hh antagonists and point out the current hurdles and future perspectives in the light of redesigning Hh-targeting therapies for the treatment of PDAC patients.