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Purpose: Patients with pancreatic cancer (PC) can be classified into various molecular subtypes and benefit from some precise therapy. Nevertheless, the interaction between metabolic and immune subtypes in the tumor microenvironment (TME) remains unknown. We hope to identify molecular subtypes related to metabolism and immunity in pancreatic cancer Methods: Unsupervised consensus clustering and ssGSEA analysis were utilized to construct molecular subtypes related to metabolism and immunity. Diverse metabolic and immune subtypes were characterized by distinct prognoses and TME. Afterward, we filtrated the overlapped genes based on the differentially expressed genes (DEGs) between the metabolic and immune subtypes by lasso regression and Cox regression, and used them to build risk score signature which led to PC patients was categorized into high- and low-risk groups. Nomogram were built to predict the survival rates of each PC patient. RT-PCR, in vitro cell proliferation assay, PC organoid, immunohistochemistry staining were used to identify key oncogenes related to PC Results: High-risk patients have a better response for various chemotherapeutic drugs in the Genomics of Drug Sensitivity in Cancer (GDSC) database. We built a nomogram with the risk group, age, and the number of positive lymph nodes to predict the survival rates of each PC patient with average 1-year, 2-year, and 3-year areas under the curve (AUCs) equal to 0.792, 0.752, and 0.751. FAM83A, KLF5, LIPH, MYEOV were up-regulated in the PC cell line and PC tissues. Knockdown of FAM83A, KLF5, LIPH, MYEOV could reduce the proliferation in the PC cell line and PC organoids Conclusion: The risk score signature based on the metabolism and immune molecular subtypes can accurately predict the prognosis and guide treatments of PC, meanwhile, the metabolism-immune biomarkers may provide novel target therapy for PC [ABSTRACT FROM AUTHOR]

Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is an aggressive and malignant tumor with an exceedingly high mortality rate. The quality of life and survival rates of pancreatic cancer patients with metastasis are poor compared with those without metastasis. Thus far, no effective treatment strategy has been established for metastatic pancreatic cancer patients. Therefore, an appropriate therapeutic method based on the elimination of metastatic pancreatic cancer is critical to improve patient outcome. Tumor-targeted vaccines have been widely discussed in recent studies and enabled important breakthroughs in the treatment of pancreatic cancer by preventing the escape of tumor cells from immune surveillance and activating the immune system to eliminate cancer cells. T cells can be activated by the stimulation of tumor-targeted vaccines, but to mount an effective immune response, both immune checkpoint inhibitors and positive costimulatory molecules are required. In this review, we discuss potential tumor-targeted vaccines that can target pancreatic cancer, elaborate the probably appropriate combination of vaccines therapy and evaluate the underlying benefits as well as obstacles in the current therapy for metastatic pancreatic cancer. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is currently one of the most lethal diseases. In recent years, increasing evidence has shown that reprogrammed metabolism may play a critical role in the carcinogenesis, progression, treatment and prognosis of pancreatic cancer. Affected by internal or external factors, pancreatic cancer cells adopt extensively distinct metabolic processes to meet their demand for growth. Rewired glucose, amino acid and lipid metabolism and metabolic crosstalk within the tumor microenvironment contribute to unlimited pancreatic tumor progression. In addition, the metabolic reprogramming involved in pancreatic cancer resistance is also closely related to chemotherapy, radiotherapy and immunotherapy, and results in a poor prognosis. Reflective of the key role of metabolism, the number of preclinical and clinical trials about metabolism-targeted therapies for pancreatic cancer is increasing. The poor prognosis of pancreatic cancer patients might be largely improved after employing therapies that regulate metabolism. Thus, investigations of metabolism not only benefit the understanding of carcinogenesis and cancer progression but also provide new insights for treatments against pancreatic cancer. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma is prone to distant metastasis and is expected to become the second leading cause of cancer-related death. In an extremely nutrient-deficient and hypoxic environment resulting from uncontrolled growth, vascular disturbances and desmoplastic reactions, pancreatic cancer cells utilize "metabolic reprogramming" to satisfy their energy demand and support malignant behaviors such as metastasis. Notably, pancreatic cancer cells show extensive enhancement of glycolysis, including glycolytic enzyme overexpression and increased lactate production, and this is caused by mitochondrial dysfunction, cancer driver genes, specific transcription factors, a hypoxic tumor microenvironment and stromal cells, such as cancer-associated fibroblasts and tumor-associated macrophages. The metabolic switch from oxidative phosphorylation to glycolysis in pancreatic cancer cells regulates the invasion–metastasis cascade by promoting epithelial–mesenchymal transition, tumor angiogenesis and the metastatic colonization of distant organs. In addition to aerobic glycolysis, oxidative phosphorylation also plays a critical role in pancreatic cancer metastasis in ways that remain unclear. In this review, we expound on the intracellular and extracellular causes of the enhancement of glycolysis in pancreatic cancer and the strong association between glycolysis and cancer metastasis, which we expect will yield new therapeutic approaches targeting cancer metabolism. [ABSTRACT FROM AUTHOR]

Long non-coding RNA LINC00657 has a critical role in multiple cancers. The aim of the present study was to investigate the regulatory effect of LINC00657 in pancreatic cancer (PC) and reveal its molecular mechanism of function. The expression levels of LINC00657 and microRNA (miR)-520h were detected by reverse transcription-quantitative PCR in PC tissues and cell lines. MTT, wound healing and Transwell assays were used to detect cell viability, migration and invasion, respectively. Dual-luciferase reporter assay was utilized to examine the relationship between LINC00657 and miR-520h and that between miR-520h and cyclin-dependent kinases regulatory subunit 1 (CKS1B). Western blotting was performed to detect CKS1B expression. The expression levels of LINC00657 and CKS1B were enhanced and miR-520h expression level was reduced in PC tissues and cell lines compared with adjacent normal tissues or HPDE6 cells. LINC00657 knockdown decreased the viability, migration and invasion of PC cells. Additionally, LINC00657 targeted miR-520h and negatively modulated miR-520h expression. Furthermore, miR-520h overexpression inhibited the viability, migration and invasion of PC cells. In addition, miR-520h targeted CKS1B and reversely regulated CKS1B expression. miR-520h inhibition and CKS1B overexpression alleviated the inhibition effect of LINC00657 knockdown on the viability, migration and invasion of PACA-2 PC cells. In conclusion, the results of the present study demonstrated that LINC00657 knockdown repressed the viability, migration and invasion of PC cells via targeting the miR-520h/CKS1B axis, which may offer a future target for PC therapy. [ABSTRACT FROM AUTHOR]

The first-line chemotherapies for patients with unresectable pancreatic cancer (PC) are 5-fluorouracil (5-FU) and gemcitabine therapy. However, due to chemoresistance the prognosis of patients with PC has not been significantly improved. Mitochondria are essential organelles in eukaryotes that evolved from aerobic bacteria. In recent years, many studies have shown that mitochondria play important roles in tumorigenesis and may act as chemotherapeutic targets in PC. In addition, according to recent studies, mitochondria may play important roles in the chemoresistance of PC by affecting apoptosis, metabolism, mtDNA metabolism, and mitochondrial dynamics. Interfering with some of these factors in mitochondria may improve the sensitivity of PC cells to chemotherapeutic agents, such as gemcitabine, making mitochondria promising targets for overcoming chemoresistance in PC. [ABSTRACT FROM AUTHOR]