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Familial pancreatic cancer (FPC) represents a significant yet underexplored area in pancreatic cancer research. Basic research efforts are notably limited, and when present, they are predominantly centered on the BRCA1 and BRCA2 mutations due to the scarcity of other genetic variants associated with FPC, leading to a limited understanding of the broader genetic landscape of FPC. This review examines the current state of FPC research, focusing on the molecular mechanisms driving pancreatic ductal adenocarcinoma (PDAC) progression. It highlights the role of homologous recombination (HR) and its therapeutic exploitation via synthetic lethality with PARP inhibitors in BRCA1/2-deficient tumors. The review discusses various pre-clinical models of FPC, including conventional two-dimensional (2D) cell lines, patient-derived organoids (PDOs), patient-derived xenografts (PDXs), and genetically engineered mouse models (GEMMs), as well as new advancements in FPC research. [ABSTRACT FROM AUTHOR]

Simple Summary: In pancreatic ductal adenocarcinoma (PDAC), the interaction between tumor cells and the tumor microenvironment is critical in regulating cancer progression. In particular, cancer-associated fibroblasts (CAFs) affect the invasive activity and resistance to chemotherapy of tumor cells by means of contact-mediated and paracrine signals, the latter including transforming growth factor beta (TGF-β). By using advanced transwell and spheroid co-culture models as exploratory tools, we showed while that TGF-β is involved in the interplay between PDAC cells and fibroblasts and promotes the acquisition of aggressive phenotypes, additional as-yet-unknown factors play a role. We propose that these advanced cell culture models provide a pathologically relevant tractable system to investigate the role of the tumor microenvironment in PDAC progression and develop novel treatment strategies. Background: The interaction between cancer cells and cancer-associated fibroblasts (CAFs) is a key determinant of the rapid progression, high invasiveness, and chemoresistance of aggressive desmoplastic cancers such as pancreatic ductal adenocarcinoma (PDAC). Tumor cells are known to reprogram fibroblasts into CAFs by secreting transforming growth factor beta (TGF-β), amongst other cytokines. In turn, CAFs produce soluble factors that promote tumor-cell invasiveness and chemoresistance, including TGF-β itself, which has a major role in myofibroblastic CAFs. Such a high level of complexity has hampered progress toward a clear view of the TGFβ signaling loop between stromal fibroblasts and PDAC cells. Methods: Here, we tackled this issue by using co-culture settings that allow paracrine signaling alone (transwell systems) or paracrine and contact-mediated signaling (3D spheroids). Results: We found that TGF-β is critically involved in the activation of normal human fibroblasts into alpha-smooth muscle actin (α-SMA)-positive CAFs. The TGF-β released by CAFs accounted for the enhanced proliferation and resistance to gemcitabine of PDAC cells. This was accompanied by a partial epithelial-to-mesenchymal transition in PDAC cells, with no increase in their migratory abilities. Nevertheless, 3D heterospheroids comprising PDAC cells and fibroblasts allowed monitoring the pro-invasive effects of CAFs on cancer cells, possibly due to combined paracrine and physical contact-mediated signals. Conclusions: We conclude that TGF-β is only one of the players that mediates the communication between PDAC cells and fibroblasts and controls the acquisition of aggressive phenotypes. Hence, these advanced in vitro models may be exploited to further investigate these events and to design innovative anti-PDAC therapies. [ABSTRACT FROM AUTHOR]

Associations between inflammation and cancer were first discovered approximately 160 years ago by Rudolf Virchow, who observed that tumors were infiltrated with inflammatory cells, and defined inflammation as a pathological condition. Inflammation has now emerged as one of the key mediators in oncogenesis and tumor progression, including pancreatic ductal adenocarcinoma (PDAC). However, the role of inflammatory processes in cancers is complicated and controversial, and the detailed regulatory mechanisms are still unclear. This review elucidates the dynamic interplay between inflammation and immune regulation, microenvironment alteration, metabolic reprogramming, and microbiome risk factors in PDAC, committing to exploring a deeper understanding of the role of crucial inflammatory pathways and molecules for providing insights into therapeutic strategies. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is almost entirely resistant to conventional chemotherapy and radiation therapy. A significant factor in this resistance appears to be the dense desmoplastic stroma, which contains various cancer-associated fibroblast (CAF) populations. However, our understanding of the communication between tumor cells and CAFs that contributes to this aggressive malignancy is still developing. Recently, we used an advanced three-dimensional heterospecies, heterospheroid co-culture model to investigate the signaling between human pancreatic tumor Panc1 cells and mouse pancreatic stellate cells (mPSCs) through global expression profiling. Upon discovering that CCN1 was significantly upregulated in Panc1 cells during co-culture, we decided to explore the role of CCN1 using CRISPR-Cas9 knockout technology. Panc1 cells lacking CCN1 showed reduced differentiation and decreased sensitivity to gemcitabine, primarily due to lower expression of genes involved in gemcitabine transport and metabolism. Additionally, we observed that stimulation with TGF-β1 and lysophosphatidic acid increased CCN1 expression in Panc1 cells and induced a shift in mPSCs towards a more myofibroblastic CAF-like phenotype. [ABSTRACT FROM AUTHOR]

Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), remains a highly lethal malignancy with limited therapeutic options and a dismal prognosis. By targeting the underlying molecular abnormalities responsible for PDAC development and progression, gene therapy offers a promising strategy to overcome the challenges posed by conventional radiotherapy and chemotherapy. This study sought to explore the therapeutic potential of small activating RNAs (saRNAs) specifically targeting the CCAAT/enhancer-binding protein alpha (CEBPA) gene in PDAC. To overcome the challenges associated with saRNA delivery, tetrahedral framework nucleic acids (tFNAs) were rationally engineered as nanocarriers. These tFNAs were further functionalized with a truncated transferrin receptor aptamer (tTR14) to enhance targeting specificity for PDAC cells. The constructed tFNA-based saRNA formulation demonstrated exceptional stability, efficient saRNA release ability, substantial cellular uptake, biocompatibility, and nontoxicity. In vitro experiments revealed successful intracellular delivery of CEBPA-saRNA utilizing tTR14-decorated tFNA nanocarriers, resulting in significant activation of tumor suppressor genes, namely, CEBPA and its downstream effector P21, leading to notable inhibition of PDAC cell proliferation. Moreover, in a mouse model of PDAC, the tTR14-decorated tFNA-mediated delivery of CEBPA-saRNA effectively upregulated the expression of the CEBPA and P21 genes, consequently suppressing tumor growth. These compelling findings highlight the potential utility of saRNA delivered via a designed tFNA nanocarrier to induce the activation of tumor suppressor genes as an innovative therapeutic approach for PDAC. [ABSTRACT FROM AUTHOR]

Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a consensus in clinical trials to explore how to arouse anti-tumor immunity and meanwhile overcome the poorly tumoricidal effect and the stroma barrier that greatly hinders drug penetration. To address this challenge, a comprehensive strategy is proposed to fully utilize both the ferroptotic vulnerability of PDAC to potently irritate anti-tumor immunity and the desmoplasia-associated focal adhesion kinase (FAK) to wholly improve the immunosuppressive microenvironment via sustained release of drugs in an injectable hydrogel for increasing drug penetration in tumor location and averting systematic toxicity. The injectable hydrogel ED-M@CS/MC is hybridized with micelles loaded with erastin that exclusively induces ferroptosis and a FAK inhibitor defactinib for inhibiting stroma formation, and achieves sustained release of the drugs for up to 12 days. With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and KrasG12D-engineered primary PDAC mice and synergistically promotes the infiltration of CD8+ cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC. [ABSTRACT FROM AUTHOR]

Ferroptosis is a newly discovered form of regulatory cell death characterized by excessive iron-dependent lipid peroxidation. In the past decade, significant breakthroughs have been made in comprehending the features and regulatory mechanisms of ferroptosis, and it has been confirmed that ferroptosis plays a pivotal role in the pathophysiological processes of various diseases, including tumors, inflammation, neurodegenerative diseases, and infectious diseases. The pancreas, which is the second largest digestive gland in the human body and has both endocrine and exocrine functions, is a vital organ for controlling digestion and metabolism. In recent years, numerous studies have confirmed that ferroptosis is closely related to pancreatic diseases, which is attributed to abnormal iron accumulation, as an essential biochemical feature of ferroptosis, is often present in the pathological processes of various pancreatic exocrine and endocrine diseases and the vulnerability of the pancreas to oxidative stress stimulation and damage. Therefore, comprehending the regulatory mechanism of ferroptosis in pancreatic diseases may provide valuable new insights into treatment strategies. In this review, we first summarize the hallmark features of ferroptosis and then analyze the exact mechanisms by which ferroptosis is precisely regulated at multiple levels and links, including iron metabolism, lipid metabolism, the GPX4-mediated ferroptosis defense system, the GPX4-independent ferroptosis defense system, and the regulation of autophagy on ferroptosis. Finally, we discuss the role of ferroptosis in the occurrence and development of pancreatic diseases and summarize the feasibility and limitations of ferroptosis as a therapeutic target for pancreatic diseases. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive solid tumors with a dismal prognosis and an increasing incidence. At the time of diagnosis, more than 85% of patients are in an unresectable stage. For these patients, chemotherapy can prolong survival by only a few months. Unfortunately, in recent decades, no groundbreaking therapies have emerged for PDAC, thus raising the question of how to identify novel therapeutic druggable targets to improve prognosis. Recently, the tumor microenvironment and especially its neural component has gained increasing interest in the pancreatic cancer field. A histological hallmark of PDAC is perineural invasion (PNI), whereby cancer cells invade surrounding nerves, providing an alternative route for metastatic spread. The extent of PNI has been positively correlated with early tumor recurrence and reduced overall survival. Multiple studies have shown that mechanisms involved in PNI are also involved in tumor spread and pain generation. Targeting these pathways has shown promising results in alleviating pain and reducing PNI in preclinical models. In this review, we will describe the mechanisms and future treatment strategies to target this mutually trophic interaction between cancer cells to open novel avenues for the treatment of patients diagnosed with PDAC. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high mortality rate and a poor prognosis. The human microbiota has been confirmed to participate in oncogenesis and may influence the treatment response to both chemotherapy and immunotherapy. Evidence for the association of the microbiota with PDAC risk, tumorigenesis, treatment response, and survival period is rapidly emerging. The oral microbiota and gut microbiota have the potential to be used in early diagnosis and risk stratification. Intratumor microbiota-targeted intervention strategies may be used as adjuvants to current treatments to improve therapeutic efficacy and overall survival. Here, we summarize the effect and association of the oral, gut and intratumor microbiota on the oncogenesis, progression and treatment of PDAC, as well as the potential of the microbiota to serve as a biomarker for the diagnosis and prognosis of PDAC, as well as a therapeutic target. [ABSTRACT FROM AUTHOR]

This study aims to summarize the modifiable risk factors for pancreatic ductal adenocarcinoma (PDAC) that have been known for a long time, as well as information from the most recent reports. As a cancer with a late diagnosis and poor prognosis, accurate analysis of PDAC risk factors is warranted. The incidence of this cancer continues to rise, and the five-year survival rate is the lowest with respect to other tumors. The influence of cigarette smoking, alcohol consumption, and chronic pancreatitis in increasing the risk of pancreatic ductal adenocarcinoma is continually being confirmed. There are also newly emerging reports relating to the impact of lifestyle, including physical activity, the gut and oral microbiome, and hepatotropic viruses. A precise understanding of PDAC risk factors can help to identify groups of high-risk patients, and this may contribute to population awareness and education as well as earlier diagnoses with possible better treatment outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer ranks as the fourth leading cause of cancer-related death in the United States. In fact, it is estimated that there will be 64,050 new cases and 50,550 deaths in 2023 in the US alone. Pancreatic ductal adenocarcinoma accounts for the vast majority of pancreatic cancer cases, and it has been widely recognized as one of the most devastating malignancies. The majority of patients are diagnosed at late stages when metastasis has occurred, leading to the 5-year survival rate being below 10%, which is the lowest among all cancer types. The causes of death are largely attributed to scanty screening diagnostic tools, abrupt metastasis, and prevalent chemoresistance. Molecular studies have elucidated that the stiff fibroblastic stroma shields from the penetration of therapeutic agents and establishes a hypoxic niche. A growing body of evidence identifies that tumor-associated macrophages play pivotal roles contributing to mortality by strengthening the fibroblastic stroma, promoting malignant cell proliferation, augmenting angiogenesis, metastasis, acquiring pleiotropic pancreatic cancer stem-like cells, supporting chemoresistance, and harnessing an immune-suppressive microenvironment that subsequently dampens chemo- and immunotherapies. This review will summarize research findings revealing various mechanisms employed to polarize macrophages to tumor-supporting subtypes which subsequently unleash the plethora of neoplastic characteristics. In addition, it will ignite potential targets aiming to correct the aberrant carcinogenic regulators through therapeutic approaches. Mounting evidence links the phenomenon of enhanced recruitment of tumor-associated macrophages towards cancer bulks to neoplastic growth, invasion, metastasis, immune escape, matrix remodeling, and therapeutic resistance. In the context of cancer progression, naïve macrophages are polarized into M1 or M2 subtypes according to their differentiation status, gene signatures, and functional roles. While the former render proinflammatory and anticancer effects, the latter subpopulation elicits an opposite impact on pancreatic ductal adenocarcinoma. M2 macrophages have gained increasing attention as they are largely responsible for molding an immune-suppressive landscape. Through positive feedback circuits involving a paracrine manner, M2 macrophages can be amplified by and synergized with neighboring neoplastic cells, fibroblasts, endothelial cells, and non-cell autonomous constituents in the microenvironmental niche to promote an advanced disease state. This review delineates the molecular cues expanding M2 populations that subsequently convey notorious clinical outcomes. Future therapeutic regimens shall comprise protocols attempting to abolish environmental niches favoring M2 polarization; weaken cancer growth typically assisted by M2; promote the recruitment of tumoricidal CD8+ T lymphocytes and dendritic cells; and boost susceptibility towards gemcitabine as well as other chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a few curative options. Desmoplastic stroma and immune system evasion in PDAC represent challenges to the success of therapeutic strategies are used to suitably treat other tumor types. Characterizing the PDAC microenvironment (including the immune environment) remains critical to developing safe and efficient therapies. Here, we present a comprehensive meta-analysis identifying 1153 significantly dysregulated genes, which mainly impact extracellular matrix remodeling and the immune system. We identify two signatures of twenty-eight immune-related genes and eleven stroma-related genes influencing PDAC patients' survival. Additionally, five immune genes are associated with PDAC prognosis for the first time. Pancreatic ductal adenocarcinoma (PDAC) prognoses and treatment responses remain devastatingly poor due partly to the highly heterogeneous, aggressive, and immunosuppressive nature of this tumor type. The intricate relationship between the stroma, inflammation, and immunity remains vaguely understood in the PDAC microenvironment. Here, we performed a meta-analysis of stroma-, and immune-related gene expression in the PDAC microenvironment to improve disease prognosis and therapeutic development. We selected 21 PDAC studies from the Gene Expression Omnibus and ArrayExpress databases, including 922 samples (320 controls and 602 cases). Differential gene enrichment analysis identified 1153 significant dysregulated genes in PDAC patients that contribute to a desmoplastic stroma and an immunosuppressive environment (the hallmarks of PDAC tumors). The results highlighted two gene signatures related to the immune and stromal environments that cluster PDAC patients into high- and low-risk groups, impacting patients' stratification and therapeutic decision making. Moreover, HCP5, SLFN13, IRF9, IFIT2, and IFI35 immune genes are related to the prognosis of PDAC patients for the first time. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer remains the leading cause of cancer death globally. With no reliable early detection strategy and limited treatment options, up to 90% of patients will lose their lives to this disease. In this review, we bring together recent advances in understanding the pancreatic cancer tumor microenvironment, highlighting a protein that was recently discovered to potently attenuate pancreatic cancer progression by influencing its cross-talk with the microenvironment. Pancreatic cancer (PaC) is a highly aggressive disease, with poor response to current treatments and 5-year survival rates of 10–15%. PaC progression is facilitated by its interaction with the complex and multifaceted tumor microenvironment (TME). In the TME, cancer cells and surrounding stromal cells constantly communicate with each other via the secretion and uptake of factors including cytokines, chemokines, growth factors, metabolites, and extracellular vesicles (EVs), reshaping the landscape of PaC. Recent studies demonstrated that the metastasis suppressor N-myc downstream regulated 1 (NDRG1) not only inhibits oncogenic signaling pathways in PaC cells but also alters the communication between PaC cells and the surrounding stroma. In fact, NDRG1 was found to influence the secretome of PaC cells, alter cancer cell metabolism, and interfere with intracellular trafficking and intercellular communication between PaC cells and surrounding fibroblasts. This review will present recent advancements in understanding the role of NDRG1 in PaC progression, with a focus on how this molecule influences PaC-stroma communication and its potential for re-shaping the PaC TME. [ABSTRACT FROM AUTHOR]

Simple Summary: The current methods for assessing tumor microenvironments (TMEs) using cellular markers and cell density-based assays do not identify the primitive phenotypes of single cells with multilineage selectivity or functional or cellular spatial information in tissues. Here, we combined the strategy of multiplex IHC imaging and cytometry-based cell quantification to assess multiple lineage-selective and functional phenotypic biomarkers and deeply dissect the state of immune complexity in the TME in association with clinical outcomes. Our findings showed that the percentage of CD8+ T cells expressing the T cell exhaustion marker PD-1 and/or the high expression of the checkpoint PD-L1 among CD68+ cells was associated with poor prognosis. The prognostic value of this combined approach is greater than that of lymphocyte and myeloid cell density analyses. Furthermore, a spatial analysis revealed that the abundance of PD-L1+CD68+ tumor-associated macrophages correlated with PD-1+CD8+ T cell infiltration levels. Our findings further strengthen the evidence for applying IHC imaging and cytometry-based cell analyses in precision medicine. Immune complexity status in the TME has been linked to clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. TME assessments with current cell marker and cell density-based analyses do not identify the original phenotypes of single cells with multilineage selectivity, the functional status of the cells, or cellular spatial information in the tissues. Here, we describe a method that circumvents these problems. The combined strategy of multiplexed IHC with computational image cytometry and multiparameter cytometric quantification allows us to assess multiple lineage-selective and functional phenotypic biomarkers in the TME. Our study revealed that the percentage of CD8+ T lymphoid cells expressing the T cell exhaustion marker PD-1 and the high expression of the checkpoint PD-L1 in CD68+ cells are associated with a poor prognosis. The prognostic value of this combined approach is more significant than that of lymphoid and myeloid cell density analyses. In addition, a spatial analysis revealed a correlation between the abundance of PD-L1+CD68+ tumor-associated macrophages and PD-1+CD8+T cell infiltration, indicating pro-tumor immunity associated with a poor prognosis. These data highlight the implications of practical monitoring for understanding the complexity of immune cells in situ. Digital imaging and multiparameter cytometric processing of cell phenotypes in the TME and tissue architecture can reveal biomarkers and assessment parameters for patient stratification. [ABSTRACT FROM AUTHOR]

Simple Summary: In cancer therapy, mitochondrial metabolism has emerged as a particularly attractive target, especially for malignancies such as pancreatic ductal adeno carcinoma (PDAC) that are resistant to treatment. Along with other treatment approaches, including targeting glutamine and fatty acid metabolism and inhibiting the tricarboxylic acid (TCA) cycle precursors, mitochondrial oxidative phosphorylation (OXPHOS) is still a key target in cancer therapy. To the advantage of PDAC patients, innovative and more effective therapeutics will be possible with a greater understanding of how pancreatic cancer cells control mitochondrial metabolism, and their role in PDAC progression through modulating cellular dynamics, bioenergetics, immune education, and retrograde signaling. Pancreatic ductal adenocarcinoma (PDAC), the fourteenth most common malignancy, is a major contributor to cancer-related death with the utmost case fatality rate among all malignancies. Functional mitochondria, regardless of their complex ecosystem relative to normal cells, are essential in PDAC progression. Tumor cells' potential to produce ATP as energy, despite retaining the redox potential optimum, and allocating materials for biosynthetic activities that are crucial for cell growth, survival, and proliferation, are assisted by mitochondria. The polyclonal tumor cells with different metabolic profiles may add to carcinogenesis through inter-metabolic coupling. Cancer cells frequently possess alterations in the mitochondrial genome, although they do not hinder metabolism; alternatively, they change bioenergetics. This can further impart retrograde signaling, educate cell signaling, epigenetic modifications, chromatin structures, and transcription machinery, and ultimately satisfy cancer cellular and nuclear demands. To maximize the tumor microenvironment (TME), tumor cells remodel nearby stromal cells and extracellular matrix. These changes initiate polyclonality, which is crucial for growth, stress response, and metastasis. Here, we evaluate all the intrinsic and extrinsic pathways drawn by mitochondria in carcinogenesis, emphasizing the perspectives of mitochondrial metabolism in PDAC progression and treatment. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is a cancer of the digestive system, and pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90% of all PC cases. Exosomes derived from PDAC (PDAC‐exosomes) promote PDAC development and metastasis. Exosomes are nanoscale vesicles secreted by most cells, which can carry biologically active molecules and mediate communication and cargo transportation among cells. Recent studies have focused on transforming exosomes into good drug delivery systems (DDSs) to improve the clinical treatment of PDAC. This review considers PDAC as the main research object to introduce the role of PDAC‐exosomes in PDAC development and metastasis. This review focuses on the following two themes: (a) the great potential of PDAC‐exosomes as new diagnostic markers for PDAC, and (b) the transformation of exosomes into potential DDSs. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is a highly lethal cancer and less than 10% of patients survive the 5-year mark. The molecular and biological underpinnings leading to this dismal prognosis are well-described, however, translation of these findings with subsequent improvement of the poor prognosis has been slow. The complex and dynamic accumulation of microbes, also called the microbiome, has recently attracted scientific interest in the pathogenesis of several diseases including pancreatic cancer. Since then, a limited number of significant findings were published pointing towards an important role of the microbiome in cancer, in particular pancreatic cancer. Here, we provide a concise synopsis of the current findings focusing exclusively on pancreatic cancer, and also highlight the pitfalls of microbiome research for scientists as well as clinicians to foster standardization and comparability amongst microbiome studies. Microorganisms have been increasingly implicated in the pathogenesis of malignant diseases, potentially affecting different hallmarks of cancer. Despite the fact that we have recently gained tremendous insight into the existence and interaction of the microbiome with neoplastic cells, we are only beginning to understand and exploit this knowledge for the treatment of human malignancies. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor with limited therapeutic options and a poor long-term survival. Recent data have revealed fascinating insights into the role of the tumoral microbiome in PDAC, with profound implications for survival and potentially therapeutic outcomes. In this review, we outline the current scientific knowledge about the clinical and translational role of the microbiome in PDAC. We describe the microbial compositions in healthy and tumoral pancreatic tissue and point out four major aspects of the microbiome in PDAC: pathogenesis, diagnosis, treatment, and prognosis. However, caution must be drawn to inherent pitfalls in analyzing the intratumoral microbiome. Among others, contamination with environmental microbes is one of the major challenges. To this end, we discuss different decontamination approaches that are crucial for clinicians and scientists alike to foster applicability and physiological relevance in this translational field. Without a definition of an exact and reproducible intratumoral microbial composition, the exploitation of the microbiome as a diagnostic or therapeutic tool remains theoretical. [ABSTRACT FROM AUTHOR]

Background: Mounting research studies have suggested the indispensable roles of N6-methyladenosine (m6A) RNA modification in carcinogenesis. Nevertheless, it was little known about the potential function of m6A-related lncRNAs in sample clustering, underlying mechanism, and anticancer immunity of pancreatic ductal adenocarcinoma (PDAC). Methods: PDAC sample data were obtained from TCGA-PAAD project, and a total of 23 m6A regulators were employed based on published articles. Pearson correlation and univariate Cox regression were analyzed to determine m6Arelated lncRNAs with prognostic significance to identify distinct m6A-related lncRNA subtypes by consensus clustering. Next, the least absolute shrinkage and selection operator (LASSO) algorithm was applied for constructing an m6Arelated lncRNA scoring system, further quantifying the m6A-related lncRNA patterns in individual samples. Gene set variation analysis (GSVA) was employed to assign pathway activity estimates to individual samples. To decode the comprehensive landscape of TME, the CIBERSORT method and ESTIMATE algorithm were analyzed. The half-maximal inhibitory concentration (IC50) of chemotherapeutic agents was predicted with the R package pRRophetic. Finally, a quantitative real-time polymerase chain reaction was used to determine TRPC7-AS1 mRNA expression in PDAC. Results: Two distinctm6A-related lncRNA patternswith different clinical outcomes, TEM features, and biological enrichment were identified based on 45 prognostic m6A-related lncRNAs. The identification of m6A-related lncRNA patterns within individual samples based on risk scores contributed to revealing biological signatures, clinical outcomes, TEM characterization, and chemotherapeutic effects. A prognostic risk-clinical nomogram was constructed and confirmed to estimate m6A-related lncRNA patterns in individual samples. Finally, the biological roles of TRPC7-AS1 were revealed in PDAC. Conclusion: This work comprehensively elucidated that m6A-related lncRNA patterns served as an indispensable player in prognostic prediction and TEM features. Quantitative identification of m6A-related lncRNA patterns in individual tumors will contribute to sample stratification for further optimizing therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Intercepting the molecular mechanisms implicated in pancreatic cancer progression can be an efficient therapeutic approach to treat this aggressive tumor. The Hippo pathway is a key mechanism driving tumor progression, even in the absence of KRAS activation. When this pathway is switched off, the transcriptional coactivator YAP is translocated into the nucleus and induces the activation of several genes implicated in tumor progression and apoptosis inhibition. FOSL-1 is a transcription factor that synergizes with YAP, forming a transcriptional complex. It has been shown to have a good therapeutic outcome when they are individually inhibited. In this work, we showed for the first time that the combined inhibition of YAP and FOSL-1 mRNA expression, using siRNA-lipoplexes, induces superior control over tumor growth in vitro and in vivo, compared to the individual treatments, and a reduction of the tumor stroma. The results offer a new therapeutic approach for pancreatic cancer treatment. Pancreatic cancer evades most of the current therapies and there is an urgent need for new treatments that could efficiently eliminate this aggressive tumor, such as the blocking of routes driving cell proliferation. In this work, we propose the use of small interfering RNA (siRNA) to inhibit the combined expression of FOSL-1 and YAP, two signaling proteins related with tumor cell proliferation and survival. To improve the efficacy of cell transfection, DODAB:MO (1:2) liposomes were used as siRNA nanocarriers, forming a complex denominated siRNA-lipoplexes. Liposomes and lipoplexes (carrying two siRNA for each targeted protein, or the combination of four siRNAs) were physico-chemically and biologically characterized. They showed very good biocompatibility and stability. The efficient targeting of FOSL-1 and YAP expression at both mRNA and protein levels was first proved in vitro using mouse pancreatic tumoral cell lines (KRASG12V and p53 knockout), followed by in vivo studies using subcutaneous allografts on mice. The peri-tumoral injection of lipoplexes lead to a significant decrease in the tumor growth in both Athymic Nude-Foxn1nu and C57BL/6 mice, mainly in those receiving the combination of four siRNAs, targeting both YAP and FOSL-1. These results open a new perspective to overcome the fast tumor progression in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: PDAC is one of the most malignant tumors and its treatment, whether surgery or chemotherapy, has shown poor results. Resistance to gemcitabine and other chemotherapeutic drugs is an essential factor in this failure. This review analyzes the molecular causes of gemcitabine resistance and discusses the possibilities of new approaches aimed at decreasing, delaying or even reversing chemoresistance in pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC. [ABSTRACT FROM AUTHOR]

Background: Tumour‐associated macrophages (TAMs) play an important role in promoting the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to study the epigenetic mechanisms in regulating pro‐tumour M2‐polarised TAMs in the PDAC tumour microenvironment. Methods: This study was conducted based on ex vivo TAMs isolated from PDAC tissues and in vitro THP1‐derived TAM model. RNA‐sequencing (RNA‐seq), assay for transposase‐accessible chromatin with sequencing and chromatin immunoprecipitation sequencing were performed to investigate gene expression, chromatin accessibility, transcription factor binding sites and histone modifications. Gene knockdown in THP1‐derived TAMs was performed with lentivirus, and the impact of THP1‐derived TAMs on invasion and metastasis ability of PDAC cells were investigated with in vitro and in vivo functional assays. RNA‐chromatin interaction was analysed by chromatin isolation through RNA purification with sequencing. RNA‐protein interaction was studied by RNA immunoprecipitation and RNA pull‐down. Results: Our data showed that the transcription factor CTCF (CCCTC‐binding factor) was highly expressed in TAMs and predicted to be significantly enriched in hyper‐accessible chromatin regions when compared to monocytes. High infiltration of CTCF+ TAMs was significantly associated with poor prognosis in PDAC patients. Knockdown of CTCF in THP1‐derived TAMs led to the down‐regulation of specific markers for M2‐polarised TAMs, including CD206 and CD163. When THP1‐derived TAMs with CTCF knockdown, they showed a decreased ability of invasion and metastasis. Further integrative analysis of multi‐omics data revealed that prostaglandin‐endoperoxide synthase 2 (PTGS2) and PTGS2 antisense NF‐κB1 complex‐mediated expression regulator RNA (PACERR) were critical downstream targets of CTCF and positively correlated with each other, which are closely situated on a chromosome. Knockdown of PACERR exhibited a similar phenotype as observed in CTCF knockdown THP1‐derived TAMs. Moreover, PACERR could directly bind to CTCF and recruit histone acetyltransferase E1A binding protein p300 to the promoter regions of PACERR and PTGS2, thereby enhancing histone acetylation and gene transcription, promoting the M2 polarization of TAMs in PDAC. Conclusions: Our study demonstrated a novel epigenetic regulation mechanism of promoting pro‐tumour M2‐polarised TAMs in the PDAC tumour microenvironment. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with a dismal clinical outcome. Accumulating evidence suggests that activated pancreatic stellate cells (PSCs), the major producers of extracellular matrix (ECM), drive the severe stromal/desmoplastic reaction in PDAC. Furthermore, the crosstalk among PSCs, pancreatic cancer cells (PCCs) as well as other stroma cells can establish a growth-supportive tumor microenvironment (TME) of PDAC, thereby enhancing tumor growth, metastasis, and chemoresistance via various pathways. Recently, targeting stroma has emerged as a promising strategy for PDAC therapy, and several novel strategies have been proposed. The aim of our study is to give a profound review of the role of PSCs in PDAC progression and recent advances in stroma-targeting strategies. [ABSTRACT FROM AUTHOR]

The present study investigated if c-MYC and high mobility group AT-hook 2 (HMGA2) expression was associated with prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). A total of 102 patients undergoing surgery for PDAC were retrospectively reviewed. Immunohistochemistry was used to detect c-MYC and HMGA2 protein expression in PDAC and peritumoral tissue samples. Expression of c-MYC and HMGA2 was associated with clinicopathological characteristics and prognoses of patients with PDAC using multivariate analysis. HMGA2 and c-MYC protein expression was significantly higher in PDAC tissues compared with peritumoral tissue (P<0.001). HMGA2 and c-MYC expression was also significantly higher in patients with PDAC who had lymph node metastasis, invasion of regional tissues and tumor node metastasis (TNM) stage III or IV disease compared with those who had no lymph node metastasis, no invasion of regional tissues and TNM stage I or II disease (P<0.001). Multivariate logistic regression analysis was used to identify TNM stage (P=0.007) and invasion (P=0.003) as significant independent predictors of c-MYC expression (model AUC=0.8201), and lymph node metastasis (P=0.002) and invasion (P=0.003) as significant independent predictors of HMGA2 expression (model AUC=0.7638). Cox multivariate analysis showed that expression of c-MYC (P=0.019) and HMGA2 (P<0.001), TNM stage (P=0.014) and lymph node metastasis (P=0.032) were associated with reduced overall survival time. HMGA2 and c-MYC may be important biological markers and potential therapeutic targets involved in the tumorigenesis, metastasis, invasion and prognosis of PDAC. [ABSTRACT FROM AUTHOR]

The embryonic development of all body systems is controlled by coordinated interactions of a group of genes encoding master regulators of development, which determine the fate of cells in the process of differentiation. These genes are often involved in the processes of malignant degeneration of cells. Hence, they are considered as targets of targeted gene therapy in the development of modern approaches to cancer treatment. One of the most aggressive forms of cancer is pancreatic ductal adenocarcinoma (PDAC). Thus, the study of pancreas master regulators genes is a challenging task. This review is devoted to SOX9, which is one of the key master regulators of pancreatic development and is a crucial factor in the induction and progression of PDAC. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma is one of the most lethal types of cancer with a 5-year survival rate of around 7%. Due to the relatively poor prognosis, the potential need of an effective chemoprevention is highly needed. Summary: Different risk factors like smoking or hereditary tumour syndromes should be known for early detection of pancreatic intraepithelial neoplasia. Chemopreventive dietary agents include curcumin, capsaicin and flavonoid, whereas potential chemopreventive drugs compromise aspirin, metformin or statins. This review aims to give an overview on potential risk factors for the development of pancreatic cancer. Furthermore, we try to summarise known chemopreventive agents to support the fight against this lethal disease. Key Messages: On the one hand, there are natural agents that exhibit preventive properties and can lead to the prohibition of pancreatic cancer. On the other hand, there are drugs and agents that are currently used in other contexts and are thus already approved and studied in terms of their mechanisms of effects and the related secondary effects. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine remains a cornerstone of PDAC treatment in all stages of the disease despite suboptimal clinical effects primarily caused by molecular mechanisms limiting its cellular uptake and activation and overall efficacy, as well as the development of chemoresistance within weeks of treatment initiation. To circumvent gemcitabine resistance in PDAC, several novel therapeutic approaches, including chemical modifications of the gemcitabine molecule generating numerous new prodrugs, as well as new entrapment designs of gemcitabine in colloidal systems such as nanoparticles and liposomes, are currently being investigated. Many of these approaches are reported to be more efficient than the parent gemcitabine molecule when tested in cellular systems and in vivo in murine tumor model systems; however, although promising, their translation to clinical use is still in a very early phase. This review discusses gemcitabine metabolism, activation and chemoresistance entities in the gemcitabine cytotoxicity pathway and provides an overview of approaches to override chemoresistance in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death and is the most lethal of common malignancies with a five-year survival rate of <10%. PDAC arises from different types of non-invasive precursor lesions: intraductal papillary mucinous neoplasms, mucinous cystic neoplasms and pancreatic intraepithelial neoplasia. The genetic landscape of PDAC is characterized by the presence of four frequently-mutated genes: KRAS, CDKN2A, TP53 and SMAD4. The development of mouse models of PDAC has greatly contributed to the understanding of the molecular and cellular mechanisms through which driver genes contribute to pancreatic cancer development. Particularly, oncogenic KRAS-driven genetically-engineered mouse models that phenotypically and genetically recapitulate human pancreatic cancer have clarified the mechanisms through which various mutated genes act in neoplasia induction and progression and have led to identifying the possible cellular origin of these neoplasias. Patient-derived xenografts are increasingly used for preclinical studies and for the development of personalized medicine strategies. The studies of the purification and characterization of pancreatic cancer stem cells have suggested that a minority cell population is responsible for initiation and maintenance of pancreatic adenocarcinomas. The study of these cells could contribute to the identification and clinical development of more efficacious drug treatments. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases with late diagnosis, rapid progression, high invasiveness, and early metastasis. Epithelial-to-mesenchymal transition (EMT) is a crucial step in metastasis that enables polarized immotile epithelial cells to gain fibroblast-like mesenchymal abilities such as enhanced motility. The dynamic process of EMT in PDAC with its powerful influence on disease progression and especially metastasis is of vigorous interest in biomedical research to elucidate its signaling pathways and regulation mechanisms. It is evident that epigenetics such as histone and DNA modification or noncoding RNAs such as microRNAs and long noncoding RNAs are of high importance in initiation and progress of EMT in PDAC. This review analyzes the latest research dealing with EMT and its epigenetic regulation in PDAC and summarizes its potentials in diagnostic, prognostic, and therapeutic management. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: For the small subset of pancreatic ductal adenocarcinoma (PDAC) patients with loss-of-function mutations to BRCA1/2 or PALB2, both first-line and maintenance therapy differs significantly. These mutations confer a loss of double-strand break DNA homologous recombination (HR), substantially altering drug sensitivities. In this review, we discuss the current treatment guidelines for PDAC tumors deficient in HR, as well as newly emerging strategies to improve drug responses in this population. We also highlight additional patient populations in which these strategies may also be effective, and novel strategies aiming to confer similar drug sensitivity to tumors proficient in HR repair. Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. As patients typically present with advanced disease and show poor responses to broad-spectrum chemotherapy, overall survival remains a dismal 10%. This underscores an urgent clinical need to identify new therapeutic approaches for PDAC patients. Precision medicine is now the standard of care for several difficult-to-treat cancer histologies. Such approaches involve the identification of a clinically actionable molecular feature, which is matched to an appropriate targeted therapy. Selective poly (ADP-ribose) polymerase (PARP) inhibitors such as Niraparib, Olaparib, Talazoparib, Rucaparib, and Veliparib are now approved for several cancers with loss of high-fidelity double-strand break homologous recombination (HR), namely those with deleterious mutations to BRCA1/2, PALB2, and other functionally related genes. Recent evidence suggests that the presence of such mutations in pancreatic ductal adenocarcinoma (PDAC), the most common and lethal pancreatic cancer histotype, significantly alters drug responses both with respect to first-line chemotherapy and maintenance therapy. In this review, we discuss the current treatment paradigm for PDAC tumors with confirmed deficits in double-strand break HR, as well as emerging strategies to both improve responses to PARP inhibition in HR-deficient PDAC and confer sensitivity to tumors proficient in HR repair. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is a devastating malignant disease with a dismal prognosis and limited treatment options. Around 14% of pancreatic cancers harbour mutations in specific genes that are important to ensure appropriate DNA repair after damage, like the BRCA 1 and 2 genes. Recently, with olaparib a first treatment option for BRCA 1 and 2 mutated pancreatic cancer was approved. However, there is a relevant proportion of further genes involved in the DNA damage repair beyond BRCA1 and 2 that might benefit from such tailored therapeutic interventions like olaparib. Unfortunately, due to the lack of specific data, no general recommendations are currently available. Therefore, a representative panel of experts was assembled by the European Society of Digestive Oncology (ESDO) to assess the current knowledge and evaluate the significance to treat pancreatic cancer with mutations in DNA damage repair genes. The data-driven consensus recommendations of the ESDO expert panel aim to provide clinicians guidance for a state-of-the-art management. Impaired DNA damage repair (DDR) is increasingly recognised as a hallmark in pancreatic ductal adenocarcinoma (PDAC). It is estimated that around 14% of human PDACs harbour mutations in genes involved in DDR, including, amongst others, BRCA1/2, PALB2, ATM, MSH2, MSH6 and MLH1. Recently, DDR intervention by PARP inhibitor therapy has demonstrated effectiveness in germline BRCA1/2-mutated PDAC. Extending this outcome to the significant proportion of human PDACs with somatic or germline mutations in DDR genes beyond BRCA1/2 might be beneficial, but there is a lack of data, and consequently, no clear recommendations are provided in the field. Therefore, an expert panel was invited by the European Society of Digestive Oncology (ESDO) to assess the current knowledge and significance of DDR as a target in PDAC treatment. The aim of this virtual, international expert meeting was to elaborate a set of consensus recommendations on testing, diagnosis and treatment of PDAC patients with alterations in DDR pathways. Ahead of the meeting, experts completed a 27-question survey evaluating the key issues. The final recommendations herein should aid in facilitating clinical practice decisions on the management of DDR-deficient PDAC. [ABSTRACT FROM AUTHOR]

Pancreatic stellate cells (PSCs) play a key role in desmoplastic stroma, which is a characteristic of pancreatic ductal adenocarcinoma (PDAC), and they also enhance the malignancy of pancreatic cancer cells. Our previous study reported chloroquine's mitigating effects on PSC activation; however, the drug is known to induce adverse effects in clinical practice. The present study aimed to reduce chloroquine doses and develop a useful pre-treatment that targets PSCs using nanoparticles. Poly lactic-co-glycolic acid (PLGA) nanoparticles were used as carriers and loaded with indocyanine green (Nano-ICG) or chloroquine (Nano-CQ). Tumor accumulation of Nano-ICG was evaluated using an in vivo imaging system. The effects of chloroquine, Nano-CQ and/or chemotherapy drug gemcitabine were investigated in an orthotopic xenograft mouse model. Nano-ICG selectively accumulated in pancreatic tumors and persisted therein for over 7 days after administration. Additionally, Nano-ICG accumulated in the peritoneal metastasized regions, but not in the liver, kidney and normal pancreatic tissues. Nano-CQ reduced the density of activated PSCs at lower chloroquine doses and significantly restrained tumor progression in combination with gemcitabine. In conclusion, the PLGA nanosystem successfully delivered the drug to pancreatic tumors. Nano-CQ efficiently reduced PSC activation and may be a promising novel pre-treatment strategy for PDAC. [ABSTRACT FROM AUTHOR]

Simple Summary: Macrophages are a major component of the pancreatic tumor microenvironment, and their increased abundance is associated with poor patient survival. Given the multi-faceted role of macrophages in promoting pancreatic tumor development and progression, these cells represent promising targets for anti-cancer therapy. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of less than 10%. Macrophages are one of the earliest infiltrating cells in the pancreatic tumor microenvironment, and are associated with an increased risk of disease progression, recurrence, metastasis, and shorter overall survival. Pre-clinical studies have demonstrated an unequivocal role of macrophages in PDAC by contributing to chronic inflammation, cancer cell stemness, desmoplasia, immune suppression, angiogenesis, invasion, metastasis, and drug resistance. Several macrophage-targeting therapies have also been investigated in pre-clinical models, and include macrophage depletion, inhibiting macrophage recruitment, and macrophage reprogramming. However, the effectiveness of these drugs in pre-clinical models has not always translated into clinical trials. In this review, we discuss the molecular mechanisms that underpin macrophage heterogeneity within the pancreatic tumor microenvironment, and examine the contribution of macrophages at various stages of PDAC progression. We also provide a comprehensive update of macrophage-targeting therapies that are currently undergoing clinical evaluation, and discuss clinical challenges associated with these treatment modalities in human PDAC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The lack of early diagnosis and the absence of suitable biomarkers coupled with resistance to available therapeutic options render pancreatic cancer one of the deadliest cancer types. Therefore, new therapeutic approaches are needed to be developed, taking into account the genetic and molecular profile of pancreatic tumors. Here, we critically review past and current efforts that have resulted in the development of potent and specific antitumor compounds that, if employed in the appropriate combination therapy, may change this recalcitrant cancer type into a manageable one. Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers intratumoral and intertumoral heterogeneity with distinct proliferative and metastatic propensity. This heterogeneity can explain why tumors do not behave uniformly and are able to escape therapy. The advance in technology of whole-genome sequencing has now provided the possibility of identifying every somatic mutation, copy-number change, and structural variant in a given cancer, giving rise to personalized targeted therapies. In this review, we provide an overview of the current and emerging treatment strategies in pancreatic cancer. By highlighting new paradigms in pancreatic ductal adenocarcinoma treatment, we hope to stimulate new thoughts for clinical trials aimed at improving patient outcomes. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the "hallmarks of cancer." Their expression is dysregulated in cancer, and they are "misused" to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same "profibrotic" ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Gemcitabine (GEM) is used as the gold standard drug in PDAC treatment. However, due to its poor efficacy, it remains urgent to identify novel strategies to overcome resistance issues. In this context, an intense stroma reaction and the presence of cancer stem cells (CSCs) have been shown to influence PDAC aggressiveness, metastatic potential, and chemoresistance. Methods: We used three-dimensional (3D) organotypic cultures grown on an extracellular matrix composed of Matrigel or collagen I to test the effect of the new potential therapeutic prodrug 4-(N)-stearoyl-GEM, called C18GEM. We analyzed C18GEM cytotoxic activity, intracellular uptake, apoptosis, necrosis, and autophagy induction in both Panc1 cell line (P) and their derived CSCs. Results: PDAC CSCs show higher sensitivity to C18GEM treatment when cultured in both two-dimensional (2D) and 3D conditions, especially on collagen I, in comparison to GEM. The intracellular uptake mechanisms of C18GEM are mainly due to membrane nucleoside transporters' expression and fatty acid translocase CD36 in Panc1 P cells and to clathrin-mediated endocytosis and CD36 in Panc1 CSCs. Furthermore, C18GEM induces an increase in cell death compared to GEM in both cell lines grown on 2D and 3D cultures. Finally, C18GEM stimulated protective autophagy in Panc1 P and CSCs cultured on 3D conditions. Conclusion: We propose C18GEM together with autophagy inhibitors as a valid alternative therapeutic approach in PDAC treatment. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with a specific tumor immune microenvironment (TIME). Therefore, investigating prognostic immune-related genes (IRGs) that are closely associated with TIME to predict PDAC clinical outcomes is necessary. In the present study, 459 samples of PDAC from the Genotype-Tissue Expression database, The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) were included and a survival-associated module was identified using weighted gene co-expression network analysis. Based on the Cox regression analysis and least absolute shrinkage and selection operator analysis, four IRGs (2′-5′-oligoadenylate synthetase 1, MET proto-oncogene, receptor tyrosine kinase, interleukin 1 receptor type 2 and interleukin 20 receptor subunit β) were included in the prognostic model to calculate the risk score (RS), and patients with PDAC were divided into high- and low-RS groups. Kaplan-Meier survival and receiver operating characteristic curve analyses demonstrated that the low-RS group had significantly improved survival conditions compared with the high-RS group in TCGA training set. The prognostic function of the model was also validated using ICGC and GEO cohorts. To investigate the mechanism of different overall survival between the high- and low-RS groups, the present study included Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data and Cell Type Identification by Estimating Relative Subset of Known RNA Transcripts algorithms to investigate the state of the tumor microenvironment and immune infiltration inpatients in the cohort from TCGA. In summary, four genes associated with the TIME of PDAC were identified, which may provide a reference for clinical treatment. [ABSTRACT FROM AUTHOR]

Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline BRCA1/2-mutated PDAC patients after platinum-based induction for the first time. Transferability of such a concept to other DNA damage response (DDR) genes remains unclear. Here, we conducted a placebo-controlled, three-armed preclinical trial to evaluate the efficacy of multi-DDR interference (mDDRi) as maintenance therapy vs. continuous FOLFIRINOX treatment, implemented with orthotopically transplanted ATM-deficient PDAC cell lines. Kaplan–Meier analysis, cross-sectional imaging, histology, and in vitro analysis served as analytical readouts. Median overall survival was significantly longer in the mDDRi maintenance arm compared to the maintained FOLFIRINOX treatment. This survival benefit was mirrored in the highest DNA-damage load, accompanied by superior disease control and reduced metastatic burden. In vitro analysis suggests FOLFIRINOX-driven selection of invasive subclones, erased by subsequent mDDRi treatment. Collectively, this preclinical trial substantiates mDDRi in a maintenance setting as a novel therapeutic option and extends the concept to non-germline BRCA1/2-mutant PDAC. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies due to the rapid rate of metastasis and high resistance to currently applied cancer therapies. The complex mechanism underlying the development and progression of PDAC includes interactions between genomic, epigenomic, and signaling pathway alterations. In this review, we summarize the current research findings on the deregulation of epigenetic mechanisms in PDAC and the influence of the epigenome on the dynamics of the gene expression changes underlying epithelial–mesenchymal transition (EMT), which is responsible for the invasive phenotype of cancer cells and, therefore, their metastatic potential. More importantly, we provide an overview of the studies that uncover potentially actionable pathways. These studies provide a scientific basis to test epigenetic drug efficacy in synergy with other anticancer therapies in future clinical trials, in order to reverse acquired therapy resistance. Thus, epigenomics has the potential to generate relevant new knowledge of both a biological and clinical impact. Moreover, the potential, hurdles, and challenges of predictive biomarker discoveries will be discussed, with a special focus on the promise of liquid biopsies. [ABSTRACT FROM AUTHOR]

Current standard-of-care for patients with pancreatic ductal adenocarcinoma (PDAC) focusses on chemotherapeutic regimens and pancreatic cancer surgery. However, limited treatment options, late diagnosis in advanced tumor stages and the aggressive behavior of PDAC contribute to the high mortality of the disease. Consequently, there is an urgent need of precision medicine for pancreatic cancer patients. All over the world, numerous initiatives started in recent years to translate novel scientific discoveries into prospective clinical trials. One major approach pursues the stratification of PDAC patients according the tumor transcriptome to predict treatment response. Other strategies concentrate on genomic alterations and the identification of individualized targeted therapies. Further experimental studies are ongoing to detect novel biomarkers for cancer diagnosis, subtyping, treatment response prediction or clinical outcome. However, the challenge remains to transfer the knowledge into clinical practice. In this review, we summarize current literature and knowledge and highlight novel concepts of basic and clinical research uncovering suitable biomarkers and targeted therapies. Thus, we provide an overview of preclinical and clinical efforts of precision medicine in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Next-generation sequencing has led to the recent discovery of several novel pancreatic cancer susceptibility genes. These genes include ataxia telangiectasia mutated (ATM), a serine/threonine kinase that is an integral component of DNA repair. Pathogenic germline ATM variants are frequently identified in patients with pancreatic ductal adenocarcinoma (PDAC) with and without a family history of the disease. Loss of ATM is also a frequent somatic event in the development of PDAC. These discoveries have advanced our understanding of the genetic basis of pancreatic cancer risk and will impact patient care through appropriate patient–risk stratification; personalized screening and early detection efforts; and, for some, targeted therapy. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers in the world due to late diagnosis and poor response to available treatments. It is important to identify treatment strategies that will increase the efficacy and reduce the toxicity of the currently used therapeutics. In this study, the PDAC cell lines AsPC-1, BxPC-3, and Capan-1 were treated with sorafenib and betulinic acid alone and in combination. We examined the effect of combined treatments on viability (MTS test), proliferation and apoptosis (annexin V staining), cell cycle arrest (PI staining), alterations in signaling pathways (Western blotting), and colony-forming ability. The combination of sorafenib with betulinic acid inhibited the viability and proliferation of PDAC cells without the induction of apoptosis. The antiproliferative effect, caused by G2 cell cycle arrest, was strongly associated with increased expression of p21 and decreased expression of c-Myc and cyclin D1, and was induced only by combined treatment. Additionally, decreased proliferation could also be associated with the inhibition of the P13K/Akt and MAPK signaling pathways. Importantly, combination treatment reduced the colony-forming ability of PDAC cells, as compared to both compounds alone. Collectively, we showed that combined treatment with low concentrations of sorafenib and betulinic acid had the capacity to inhibit proliferation and abolish clonogenic activity in PDAC cell lines. [ABSTRACT FROM AUTHOR]