Cancer-associated endocrine cells participate in pancreatic carcinogenesis.

BACKGROUND & AIMS: The pancreas is composed of endocrine and exocrine parts, and its interlacing structure indicates potential interaction between endocrine and exocrine cells. Although the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) has been well characterized, the role of pancreatic endocrine cells during carcinogenesis is relatively understudied. METHODS: We depicted the changes of endocrine cells in PDAC by single-cell transcriptome sequencing, spatial transcriptome sequencing and multiplex immunohistochemistry. After that, the interaction between pancreatic carcinogenesis and endocrine changes was explored in orthotopic transplantation mice, KC mice and KPC mice. Finally, we proved the mechanism of the interaction between endocrine and exocrine parts of the pancreas through islet isolation, co-culture in vitro and co-injection in vivo. RESULTS: We found that pancreatic endocrine cells displayed significantly different transcriptomic characteristics and increased interaction with exocrine part in PDAC. Specifically, among all the changes, pancreatic polypeptide positive (PPY+) cells showed a sharp increment accompanied with the progression of the cancer lesion, which might be derived from the transdifferentiation of α and ß cells. Interestingly, it was proved that PDAC cells were able to induce the transdifferentiation of pancreatic α cells and ß cells into GCG+PPY+ and INS+PPY+ double-positive cells, which further promoted carcinogenesis and development of PDAC in a paracrine-dependent manner and formed a reciprocal interaction. CONCLUSIONS: Our study systematically maps the alteration of pancreatic endocrine cells in PDAC and elucidates the potential endocrine-exocrine interaction mechanisms during PDAC carcinogenesis. Meanwhile, we first time define and characterize cancer-associated endocrine cells (CAEs), thereby further broadening the composition of PDAC microenvironment.

Cell-in-Cell-Mediated Entosis Reveals a Progressive Mechanism in Pancreatic Cancer.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with high intratumoral heterogeneity. There is a lack of effective therapeutics for PDAC. Entosis, a form of nonapoptotic regulated cell death mediated by cell-in-cell structures (CICs), has been reported in multiple cancers. However, the role of entosis in PDAC progression remains unclear. METHODS: CICs were evaluated using immunohistochemistry and immunofluorescence staining. The formation of CICs was induced by suspension culture. Through fluorescence-activated cell sorting and single-cell RNA sequencing, entosis-forming cells were collected and their differential gene expression was analyzed. Cell functional assays and mouse models were used to investigate malignant phenotypes. Clinical correlations between entosis and PDAC were established by retrospective analysis. RESULTS: Entosis was associated with an unfavorable prognosis for patients with PDAC and was more prevalent in liver metastases than in primary tumors. The single-cell RNA sequencing results revealed that several oncogenes were up-regulated in entosis-forming cells compared with parental cells. These highly entotic cells demonstrated higher oncogenic characteristics in vitro and in vivo. NET1, neuroepithelial cell transforming gene 1, is an entosis-related gene that plays a pivotal role in PDAC progression and is correlated with poor outcomes. CONCLUSIONS: Entosis is correlated with PDAC progression, especially in liver metastasis. NET1 is a newly validated entosis-related gene and a molecular marker of poor outcomes. PDAC cells generate a highly aggressive subpopulation marked by up-regulated NET1 via entosis, which may drive PDAC progression.

Liver autotransplantation and atrial reconstruction on a patient with multiorgan alveolar echinococcosis: a case report.

BACKGROUND: Alveolar echinococcosis (AE) primarily affects the liver and potentially spreads to other organs. Managing recurrent AE poses significant challenges, especially when it involves critical structures and multiple major organs. CASE PRESENTATION: We present a case of a 59-year-old female with recurrent AE affecting the liver, heart, and lungs following two previous hepatectomies, the hepatic lesions persisted, adhering to major veins, and imaging revealed additional diaphragmatic, cardiac, and pulmonary involvement. The ex vivo liver resection and autotransplantation (ELRA), first in human combined with right atrium (RA) reconstruction were performed utilizing cardiopulmonary bypass, and repairs of the pericardium and diaphragm. This approach aimed to offer a potentially curative solution for lesions previously considered inoperable without requiring a donor organ or immunosuppressants. The patient encountered multiple serious complications, including atrial fibrillation, deteriorated liver function, severe pulmonary infection, respiratory failure, and acute kidney injury (AKI). These complications necessitated intensive intraoperative and postoperative care, emphasizing the need for a comprehensive management strategy in such complicated high-risk surgeries. CONCLUSIONS: The multidisciplinary collaboration in this case proved effective and yielded significant therapeutic outcomes for a rare case of advanced hepatic, cardiac, and pulmonary AE. The combined approach of ELRA and RA reconstruction under extracorporeal circulation demonstrated distinct advantages of ELRA in treating complex HAE. Meanwhile, assessing diaphragm function during the perioperative period, especially in patients at high risk of developing pulmonary complications and undergoing diaphragmectomy is vital to promote optimal postoperative recovery. For multi-resistant infection, it is imperative to take all possible measures to mitigate the risk of AKI if vancomycin administration is deemed necessary.

Construction of a novel model based on cell-in-cell-related genes and validation of KRT7 as a biomarker for predicting survival and immune microenvironment in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is a highly malignant tumor featured with high intra-tumoral heterogeneity and poor prognosis. Cell-in-cell (CIC) structures have been reported in multiple cancers, and their presence is associated with disease progression. Nonetheless, the prognostic values and biological functions of CIC-related genes in PC remain poorly understood. METHODS: The sequencing data, as well as corresponding clinicopathological information of PC were collected from public databases. Random forest screening, least absolute shrinkage, and selection operator (LASSO) regression and multivariate Cox regression analysis were performed to construct a prognostic model. The effectiveness and robustness of the model were evaluated using receiver operating characteristic (ROC) curves, survival analysis and establishing the nomogram model. Functional enrichment analyses were conducted to annotate the biological functions. The immune infiltration levels were evaluated by ESTIMATE and CIBERSORT algorithms. The expression of KRT7 (Keratin 7) was validated by quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) staining. The CIC formation, cell clusters, cell proliferation, migration and invasion assays were applied to investigate the effects of silencing the expression of KRT7. RESULTS: A prognostic model based on four CIC-related genes was constructed to stratify the patients into the low- and high-risk subgroups. The high-risk group had a poorer prognosis, higher tumor mutation burden and lower immune cell infiltration than the low-risk group. Functional enrichment analyses showed that numerous terms and pathways associated with invasion and metastasis were enriched in the high-risk group. KRT7, as the most paramount risk gene in the prognostic model, was significantly associated with a worse prognosis of PC in TCGA dataset and our own cohort. High expression of KRT7 might be responsible for the immunosuppression in the PC microenvironment. KRT7 knockdown was significantly suppressed the abilities of CIC formation, cell cluster, cell proliferation, migration, and invasion in PC cell lines. CONCLUSIONS: Our prognostic model based on four CIC-related genes has a significant potential in predicting the prognosis and immune microenvironment of PC, which indicates that targeting CIC processes could be a therapeutic option with great interests. Further studies are needed to reveal the underlying molecular mechanisms and biological implications of CIC phenomenon and related genes in PC progression.

Construction of immune-related signature and identification of S100A14 determining immune-suppressive microenvironment in pancreatic cancer.

Pancreatic cancer (PC) is a highly lethal and aggressive disease with its incidence and mortality quite discouraging. A robust prognostic signature and novel biomarkers are urgently needed for accurate stratification of the patients and optimization of clinical decision-making. Since the critical role of immune microenvironment in the progression of PC, a prognostic signature based on seven immune-related genes was established, which was validated in The Cancer Genome Atlas (TCGA) training set, TCGA testing set, TCGA entire set and GSE71729 set. Furthermore, S100A14 (S100 Calcium Binding Protein A14) was identified as the gene occupying the most paramount position in risk signature. According to the GSEA, CIBERSORT and ESTIMATE algorithm, S100A14 was mainly associated with lower proportion of CD8 + T cells and higher proportion of M0 macrophages in PC tissue. Meanwhile, analysis of single-cell dataset CRA001160 revealed a significant negative correlation between S100A14 expression in PC cells and CD8 + T cell infiltration, which was further confirmed by tissue microenvironment landscape imaging and machine learning-based analysis in our own PUMCH cohort. Additionally, analysis of a pan-pancreatic cancer cell line illustrated that S100A14 might inhibit CD8 + T cell activation via the upregulation of PD-L1 expression in PC cells, which was also verified by the immunohistochemical results of PUMCH cohort. Finally, tumor mutation burden analysis and immunophenoscore algorithm revealed that patients with high S100A14 expression had a higher probability of responding to immunotherapy. In conclusion, our study established an efficient immune-related prediction model and identified the potential role of S100A14 in regulating the immune microenvironment and serving as a biomarker for immunotherapy efficacy prediction.

Central GLP-1 contributes to improved cognitive function and brain glucose uptake after duodenum-jejunum bypass on obese and diabetic rats.

The improvement of cognitive function following bariatric surgery has been highlighted, yet its underlying mechanisms remain elusive. Finding the improved brain glucose uptake of patients after Roux-en-Y gastric bypass (RYGB), duodenum-jejunum bypass (DJB), and sham surgery (Sham) were performed on obese and diabetic Wistar rats, and intracerebroventricular (ICV) injection of glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira), antagonist exendin-(9-39) (Exe-9), and the viral-mediated GLP-1 receptor (Glp-1r) knockdown (KD) were applied on both groups to elucidate the role of GLP-1 in mediating cognitive function and brain glucose uptake assessed with the Morris water maze (MWM) and positron emission tomography (PET). Insulin and GLP-1 in serum and cerebral spinal fluid (CSF) were measured, and the expression of glucose uptake-related proteins including glucose transporter 1 (GLUT-1), GLUT-4, phospho-Akt substrate of 160kDa (pAS160), AS160, Rab10, Myosin-Va as well as the c-fos marker in the brain were examined. Along with augmented glucose homeostasis following DJB, central GLP-1 was correlated with the improved cognitive function and ameliorated brain glucose uptake, which was further confirmed by the enhancive role of Lira on both groups whereas the Exe-9 and Glp-1r KD were opposite. Known to activate insulin-signaling pathways, central GLP-1 contributes to improved cognitive function and brain glucose uptake after DJB.NEW & NOTEWORTHY The improvement of cognitive function following bariatric surgery has been highlighted while its mechanisms remain elusive. The brain glucose uptake of patients was improved after RYGB, and the DJB and sham surgery performed on obese and diabetic Wistar rats revealed that the elevated central GLP-1 contributes to the dramatic improvement of cognitive function, brain glucose uptake, transport, glucose sensing, and neuronal activation.

Construction of a prognostic model with histone modification-related genes and identification of potential drugs in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is a highly fatal and aggressive disease with its incidence and mortality quite discouraging. An effective prediction model is urgently needed for the accurate assessment of patients' prognosis to assist clinical decision-making. METHODS: Gene expression data and clinicopathological data of the samples were acquired from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases. Differential expressed genes (DEGs) analysis, univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, random forest screening and multivariate Cox regression analysis were applied to construct the risk signature. The effectiveness and independence of the model were validated by time-dependent receiver operating characteristic (ROC) curve, Kaplan-Meier (KM) survival analysis and survival point graph in training set, test set, TCGA entire set and GSE57495 set. The validity of the core gene was verified by immunohistochemistry and our own independent cohort. Meanwhile, functional enrichment analysis of DEGs between the high and low risk groups revealed the potential biological pathways. Finally, CMap database and drug sensitivity assay were utilized to identify potential small molecular drugs as the risk model-related treatments for PC patients. RESULTS: Four histone modification-related genes were identified to establish the risk signature, including CBX8, CENPT, DPY30 and PADI1. The predictive performance of risk signature was validated in training set, test set, TCGA entire set and GSE57495 set, with the areas under ROC curve (AUCs) for 3-year survival were 0.773, 0.729, 0.775 and 0.770 respectively. Furthermore, KM survival analysis, univariate and multivariate Cox regression analysis proved it as an independent prognostic factor. Mechanically, functional enrichment analysis showed that the poor prognosis of high-risk population was related to the metabolic disorders caused by inadequate insulin secretion, which was fueled by neuroendocrine aberration. Lastly, a cluster of small molecule drugs were identified with significant potentiality in treating PC patients. CONCLUSIONS: Based on a histone modification-related gene signature, our model can serve as a reliable prognosis assessment tool and help to optimize the treatment for PC patients. Meanwhile, a cluster of small molecule drugs were also identified with significant potentiality in treating PC patients.

Sleeve gastrectomy ameliorates alveolar structures and surfactant protein expression in lungs of obese and diabetic rats.

BACKGROUND: Bariatric surgeries have been shown to be effective in reversing damaged pulmonary function in individuals suffering from obesity and type 2 diabetes mellitus, whereas its underlying mechanisms remain largely unknown. METHODS: Sleeve gastrectomy (SG) was performed on obese and diabetic Wistar rats, and their pulmonary function and lung tissues were compared to sham-operated (SH) obese and diabetic rats, and age-matched healthy controls (C) to explore the improvements in microstructures and expression of surfactant protein (SP)-A and -C at postoperative 4th, 8th, and 12th week. RESULT: Apart from the profound metabolic changes and improvement in pulmonary function, lung volume was restored along with an improved diffusion capacity noted by thinned capillary basement membrane and decreased harmonic mean length of diffusion barrier in SG rats. The digital slices of light microscope showed the general changes brought on by the SG, including normalized basic structures, ameliorated inflammatory status, as well as reduced lipid deposition, where the hydroxyproline (HYP), triglyceride (TG) assays, and electron microscope further suggested that the improvement in alveolar structures lies in reduced collagen fibers, lipids and septal tissues, increased capillary blood, and normalized alveolar type 2 (AT2) cells. Besides, disrupted SP-A and SP-C expression were also normalized after SG. CONCLUSION: The improvement of lung function after SG is related to the ameliorated alveolar structures, and surface protein expression induced by weight loss and improved glucose metabolism.

Correlation between laparoscopic transection of an indirect inguinal hernial sac and postoperative seroma formation: a prospective randomized controlled study.

BACKGROUND: Seroma is the most common early minor complication of inguinal hernia repair. Seromas generally resolve spontaneously within a few weeks, but can sometimes cause other complications. The optimal ways to repair inguinal hernia and handle the hernial sac are still debatable. Large scale, prospective, randomized, controlled studies focusing on the correlation between transection of the hernial sac and seroma formation are scarce. METHODS: A total of 159 adult male patients with primary indirect inguinal hernia who underwent laparoscopic transabdominal preperitoneal repair were recruited. The patients were randomized to undergo either complete dissection or transection of the hernial sacs. Patients were followed up at postoperative 7 days, 1 and 3 months, looking specifically for seroma. Seroma was diagnosed via physical examination, and a prestructured form was used to evaluate patient recovery and define the type of seroma present at each follow-up visit. RESULTS: There were 83 patients in the completely dissected group and 76 in the transected group. The overall incidence of postoperative seroma was 12.6% (n = 20). The χ2 test demonstrated that significantly more patients developed seroma in the transected group than in the completely dissected group (18.4% vs. 7.2%, p = 0.034); there were also significant differences between the two groups in the incidences of seroma at postoperative 7 days (18.4% vs. 6.0%, p = 0.016) and 1 month (14.5% vs. 4.8%, p = 0.037). Seroma formation was correlated with age, body mass index, use of anticoagulants, hernia type, hernia size, sac size, and operative time. There were no significant differences between the two groups in the degree of postoperative pain and time taken for the resumption of outdoor activities. CONCLUSIONS: When using the laparoscopic transabdominal preperitoneal technique for indirect inguinal hernia repair, the risk of postoperative seroma formation is greater after transection compared with complete dissection of the hernial sac.

Immune-related signature identifies IL1R2 as an immunological and prognostic biomarker in pancreatic cancer.

Objective: Pancreatic cancer is one of the most aggressive malignancies, a robust prognostic signature and novel biomarkers are urgently needed for accurate stratification of the patients and optimization of clinical decision-making. Methods: A list of bioinformatic analysis were applied in public dataset to construct an immune-related signature. Furthermore, the most pivotal gene in the signature was identified. The potential mechanism of the core gene function was revealed through GSEA, CIBERSORT, ESTIMATE, immunophenoscore (IPS) algorithm, single-cell analysis, and functional experiment. Results: An immune-related prognostic signature and associated nomogram were constructed and validated. Among the genes constituting the signature, interleukin 1 receptor type II (IL1R2) was identified as the gene occupying the most paramount position in the risk signature. Meanwhile, knockdown of IL1R2 significantly inhibited the proliferation, invasion, and migration ability of pancreatic cancer cells. Additionally, high IL1R2 expression was associated with reduced CD8+ T cell infiltration in pancreatic cancer microenvironment, which may be due to high programmed cell death-ligand-1 (PD-L1) expression in cancer cells. Finally, the IPS algorithm proved that patients with high IL1R2 expression possessed a higher tumor mutation burden and a higher probability of benefiting from immunotherapy. Conclusion: In conclusion, our study constructed an efficient immune-related prognostic signature and identified the key role of IL1R2 in the development of pancreatic cancer, as well as its potential to serve as a biomarker for immunotherapy efficacy prediction for pancreatic cancer.

Enhanced cytokine signaling and ferroptosis defense interplay initiates obesity-associated pancreatic ductal adenocarcinoma.

Obesity is a significant risk factor for various cancers, including pancreatic cancer (PC), but the underlying mechanisms are still unclear. In our study, pancreatic ductal epithelial cells were cultured using serum from human subjects with diverse metabolic statuses, revealing that serum from patients with obesity alters inflammatory cytokine signaling and ferroptosis, where a mutual enhancement between interleukin 34 (IL-34) expression and ferroptosis defense was observed in these cells. Notably, oncogenic KRASG12D amplified their interaction and this leads to the initiation of pancreatic ductal adenocarcinoma (PDAC) in diet-induced obese mice via macrophage-mediated immunosuppression. Single-cell RNA sequencing (scRNA-seq) of human samples showed that cytokine signaling, ferroptosis defense, and immunosuppression are correlated with the patients' body mass index (BMI) during PDAC progression. Our findings provide a mechanistic link between obesity, inflammation, ferroptosis defense, and pancreatic cancer, suggesting novel therapeutic targets for the prevention and treatment of obesity-associated PDAC.

Bariatric Surgery: Targeting pancreatic ß cells to treat type II diabetes.

Pancreatic ß-cell function impairment and insulin resistance are central to the development of obesity-related type 2 diabetes mellitus (T2DM). Bariatric surgery (BS) is a practical treatment approach to treat morbid obesity and achieve lasting T2DM remission. Traditionally, sustained postoperative glycemic control was considered a direct result of decreased nutrient intake and weight loss. However, mounting evidence in recent years implicated a weight-independent mechanism that involves pancreatic islet reconstruction and improved ß-cell function. In this article, we summarize the role of ß-cell in the pathogenesis of T2DM, review recent research progress focusing on the impact of Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) on pancreatic ß-cell pathophysiology, and finally discuss therapeutics that have the potential to assist in the treatment effect of surgery and prevent T2D relapse.

Mechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis: a comprehensive and systematic review.

Research on obesity- and diabetes mellitus (DM)-related carcinogenesis has expanded exponentially since these two diseases were recognized as important risk factors for cancers. The growing interest in this area is prominently actuated by the increasing obesity and DM prevalence, which is partially responsible for the slight but constant increase in pancreatic cancer (PC) occurrence. PC is a highly lethal malignancy characterized by its insidious symptoms, delayed diagnosis, and devastating prognosis. The intricate process of obesity and DM promoting pancreatic carcinogenesis involves their local impact on the pancreas and concurrent whole-body systemic changes that are suitable for cancer initiation. The main mechanisms involved in this process include the excessive accumulation of various nutrients and metabolites promoting carcinogenesis directly while also aggravating mutagenic and carcinogenic metabolic disorders by affecting multiple pathways. Detrimental alterations in gastrointestinal and sex hormone levels and microbiome dysfunction further compromise immunometabolic regulation and contribute to the establishment of an immunosuppressive tumor microenvironment (TME) for carcinogenesis, which can be exacerbated by several crucial pathophysiological processes and TME components, such as autophagy, endoplasmic reticulum stress, oxidative stress, epithelial-mesenchymal transition, and exosome secretion. This review provides a comprehensive and critical analysis of the immunometabolic mechanisms of obesity- and DM-related pancreatic carcinogenesis and dissects how metabolic disorders impair anticancer immunity and influence pathophysiological processes to favor cancer initiation.

Obesity and type 2 diabetes mellitus: connections in epidemiology, pathogenesis, and treatments.

The prevalence of obesity and diabetes mellitus (DM) has been consistently increasing worldwide. Sharing powerful genetic and environmental features in their pathogenesis, obesity amplifies the impact of genetic susceptibility and environmental factors on DM. The ectopic expansion of adipose tissue and excessive accumulation of certain nutrients and metabolites sabotage the metabolic balance via insulin resistance, dysfunctional autophagy, and microbiome-gut-brain axis, further exacerbating the dysregulation of immunometabolism through low-grade systemic inflammation, leading to an accelerated loss of functional ß-cells and gradual elevation of blood glucose. Given these intricate connections, most available treatments of obesity and type 2 DM (T2DM) have a mutual effect on each other. For example, anti-obesity drugs can be anti-diabetic to some extent, and some anti-diabetic medicines, in contrast, have been shown to increase body weight, such as insulin. Meanwhile, surgical procedures, especially bariatric surgery, are more effective for both obesity and T2DM. Besides guaranteeing the availability and accessibility of all the available diagnostic and therapeutic tools, more clinical and experimental investigations on the pathogenesis of these two diseases are warranted to improve the efficacy and safety of the available and newly developed treatments.

Obesity, diabetes mellitus, and pancreatic carcinogenesis: Correlations, prevention, and diagnostic implications.

The prevalence of obesity, diabetes mellitus (DM), and pancreatic cancer (PC) has been consistently increasing in the last two decades worldwide. Sharing various influential risk factors in genetics and environmental inducers in pathogenesis, the close correlations of these three diseases have been demonstrated in plenty of clinical studies using multiple parameters among different populations. On the contrary, most measures aimed to manage and treat obesity and DM effectively reduce the risk and prevent PC occurrence, yet certain drugs can inversely promote pancreatic carcinogenesis instead. Most importantly, an elevation of blood glucose with or without a reduction in body weight, along with other potential tools, may provide valuable clues for detecting PC at an early stage in patients with obesity and DM, favoring a timely intervention and prolonging survival. Herein, the epidemiological and etiological correlations among these three diseases and the supporting clinical evidence of their connections are first summarized to favor a better and more thorough understanding of obesity- and DM-related pancreatic carcinogenesis. After comparing the distinct impacts of different weight-lowering and anti-diabetic treatments on the risk of PC, the possible diagnostic implications of hyperglycemia and weight loss in PC screening are also addressed in detail.

SQLE promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signaling pathway.

Pancreatic cancer (PC), a highly lethal malignancy, commonly exhibits metabolic reprogramming that results in therapeutic vulnerabilities. Nevertheless, the mechanisms underlying the impacts of aberrant cholesterol metabolism on PC development and progression remain elusive. In this study, we found that squalene epoxidase (SQLE) is a crucial mediator of cholesterol metabolism in PC growth. We observed a profound upregulation of SQLE in PC tissues, and its high expression was correlated with poor patient outcomes. Our functional experiments demonstrated that SQLE facilitated cell proliferation, induced cell cycle progression, and inhibited apoptosis in vitro, while promoting tumor growth in vivo. Mechanistically, SQLE was found to have a dual role. First, its inhibition led to squalene accumulation-induced endoplasmic reticulum (ER) stress and subsequent apoptosis. Second, it enhanced de novo cholesterol biosynthesis and maintained lipid raft stability, thereby activating the Src/PI3K/Akt signaling pathway. Significantly, employing SQLE inhibitors effectively suppressed PC cell proliferation and xenograft tumor growth. In summary, this study reveals SQLE as a novel oncogene that promotes PC growth by mitigating ER stress and activating lipid raft-regulated Src/PI3K/Akt signaling pathway, highlighting the potential of SQLE as a therapeutic target for PC.

Prognostic value of glycolysis markers in pancreatic cancer: A systematic review and meta-analysis.

Introduction: Previous studies have investigated the prognostic significance of glycolysis markers in pancreatic cancer; however, conclusions from these studies are still controversial. Methods: PubMed, Embase, and Web of Science were systematically searched to investigate the prognostic role of glycolysis markers in pancreatic cancer up to May 2022. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) related to overall survival (OS), disease free survival (DFS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) were calculated using the STATA 12.0 software. Results: A total of 28 studies comprising 2010 patients were included in this meta-analysis. High expression of the five glycolysis markers was correlated with a poorer OS (HR = 1.72, 95% CI: 1.34-2.22), DFS (HR = 3.09, 95% CI: 1.91-5.01), RFS (HR = 1.73, 95% CI: 1.21-2.48) and DMFS (HR = 2.60, 95% CI: 1.09-6.20) in patients with pancreatic cancer. In subgroup analysis, it was shown that higher expression levels of the five glycolysis markers were related to a poorer OS in Asians (HR = 1.85, 95% CI: 1.46-2.35, P < 0.001) and Caucasians (HR = 1.97, 95% CI: 1.40-2.77, P < 0.001). Besides, analysis based on the expression levels of specific glycolysis markers demonstrated that higher expression levels of GLUT1 (HR = 2.11, 95% CI: 1.58-2.82, P < 0.001), MCT4 (HR = 2.26, 95% CI: 1.36-3.76, P = 0.002), and ENO1 (HR = 2.16, 95% CI: 1.28-3.66, P =0.004) were correlated with a poorer OS in patients with pancreatic cancer. Conclusions: High expression of the five glycolysis markers are associated with poorer OS, DFS, RFS and DMFS in patients with pancreatic cancer, indicating that the glycolysis markers could be potential prognostic predictors and therapeutic targets in pancreatic cancer.

Lipid metabolism in pancreatic cancer: emerging roles and potential targets.

Pancreatic cancer is one of the most serious health issues in developed and developing countries, with a 5-year overall survival rate currently <9%. Patients typically present with advanced disease due to vague symptoms or lack of screening for early cancer detection. Surgical resection represents the only chance for cure, but treatment options are limited for advanced diseases, such as distant metastatic or locally progressive tumors. Although adjuvant chemotherapy has improved long-term outcomes in advanced cancer patients, its response rate is low. So, exploring other new treatments is urgent. In recent years, increasing evidence has shown that lipid metabolism can support tumorigenesis and disease progression as well as treatment resistance through enhanced lipid synthesis, storage, and catabolism. Therefore, a better understanding of lipid metabolism networks may provide novel and promising strategies for early diagnosis, prognosis estimation, and targeted therapy for pancreatic cancer patients. In this review, we first enumerate and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in pancreatic cancer. In addition, we summarize preclinical studies and clinical trials with drugs targeting lipid metabolic systems in pancreatic cancer. Finally, we highlight the challenges and opportunities for targeting lipid metabolism pathways through precision therapies in pancreatic cancer.

The evolving view of thermogenic fat and its implications in cancer and metabolic diseases.

The incidence of metabolism-related diseases like obesity and type 2 diabetes mellitus has reached pandemic levels worldwide and increased gradually. Most of them are listed on the table of high-risk factors for malignancy, and metabolic disorders systematically or locally contribute to cancer progression and poor prognosis of patients. Importantly, adipose tissue is fundamental to the occurrence and development of these metabolic disorders. White adipose tissue stores excessive energy, while thermogenic fat including brown and beige adipose tissue dissipates energy to generate heat. In addition to thermogenesis, beige and brown adipocytes also function as dynamic secretory cells and a metabolic sink of nutrients, like glucose, fatty acids, and amino acids. Accordingly, strategies that activate and expand thermogenic adipose tissue offer therapeutic promise to combat overweight, diabetes, and other metabolic disorders through increasing energy expenditure and enhancing glucose tolerance. With a better understanding of its origins and biological functions and the advances in imaging techniques detecting thermogenesis, the roles of thermogenic adipose tissue in tumors have been revealed gradually. On the one hand, enhanced browning of subcutaneous fatty tissue results in weight loss and cancer-associated cachexia. On the other hand, locally activated thermogenic adipocytes in the tumor microenvironment accelerate cancer progression by offering fuel sources and is likely to develop resistance to chemotherapy. Here, we enumerate current knowledge about the significant advances made in the origin and physiological functions of thermogenic fat. In addition, we discuss the multiple roles of thermogenic adipocytes in different tumors. Ultimately, we summarize imaging technologies for identifying thermogenic adipose tissue and pharmacologic agents via modulating thermogenesis in preclinical experiments and clinical trials.