Cancer immunometabolism: advent, challenges, and perspective.

For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role.

SETD8 inhibits ferroptosis in pancreatic cancer by inhibiting the expression of RRAD.

BACKGROUND: As an oncogene, SETD8 can promote tumour growth and tumour cell proliferation. This study aims to reveal the relationship between SETD8 and ferroptosis in pancreatic cancer and its role in pancreatic cancer to provide a possible new direction for the comprehensive treatment of pancreatic cancer. METHODS: The downstream targets were screened by RNA sequencing analysis. Western blot, Real-time Quantitative PCR (qPCR) and immunohistochemistry showed the relationship between genes. Cell proliferation analysis and cell metabolite analysis revealed the function of genes. Chromatin immunoprecipitation (CHIP) assays were used to study the molecular mechanism. RESULTS: The potential downstream target of SETD8, RRAD, was screened by RNA sequencing analysis. A negative correlation between SETD8 and RRAD was found by protein imprinting, Real-time Quantitative PCR (qPCR) and immunohistochemistry. Through cell proliferation analysis and cell metabolite analysis, it was found that RRAD can not only inhibit the proliferation of cancer cells but also improve the level of lipid peroxidation of cancer cells. At the same time, chromatin immunoprecipitation analysis (CHIP) was used to explore the molecular mechanism by which SETD8 regulates RRAD expression. SETD8 inhibited RRAD expression. CONCLUSIONS: SETD8 interacts with the promoter region of RRAD, which epigenetically silences the expression of RRAD to reduce the level of lipid peroxidation in pancreatic cancer cells, thereby inhibiting ferroptosis in pancreatic cancer cells and resulting in poor prognosis of pancreatic cancer.

ASS1-Mediated Reductive Carboxylation of Cytosolic Glutamine Confers Ferroptosis Resistance in Cancer Cells.

Induction of ferroptosis, a recently defined form of nonapoptotic cell death caused by iron-dependent lipid peroxidation, has emerged as an anticancer strategy. Erastin is a ferroptosis activator that promotes cell death that not only depends on the depletion of cellular cysteine but also relies on mitochondrial oxidative metabolism of glutamine. Here, we demonstrate that ASS1, a key enzyme involved in the urea cycle, plays a crucial role in ferroptosis resistance. Loss of ASS1 increased the sensitivity of non-small cell lung cancer (NSCLC) cells to erastin in vitro and decreased tumor growth in vivo. Metabolomics analysis with stable isotope-labeled glutamine showed that ASS1 promotes reductive carboxylation of cytosolic glutamine and compromises the oxidative tricarboxylic acid cycle from glutamine anaplerosis, reducing mitochondrial-derived lipid reactive oxygen species. Moreover, transcriptome sequencing showed that ASS1 activates the mTORC1-SREBP1-SCD5 axis to promote de novo monounsaturated fatty acid synthesis by using acetyl-CoA derived from the glutamine reductive pathway. Treating ASS1-deficient NSCLC cells with erastin combined with arginine deprivation significantly enhanced cell death compared with either treatment alone. Collectively, these results reveal a previously unknown regulatory role of ASS1 in ferroptosis resistance and provide a potential therapeutic target for ASS1-deficient NSCLC. SIGNIFICANCE: ASS1 promotes reductive carboxylation of glutamine and confers ferroptosis resistance, providing multiple treatment options for ASS1-deficient non-small cell lung cancer.

Inhibition of the PIN1-NRF2/GPX4 axis imparts sensitivity to cisplatin in cervical cancer cells.

The incidence of cervical cancer (CC) ranks the fourth in female malignant tumors globally. Chemoresistance is one of the main causes of treatment failure in advanced recurrent CC. Prolyl isomerase 1 (PIN1) is overexpressed in a variety of tumors, and is closely associated with the malignant potential of tumor cells, such as transformation, proliferation, invasion and metastasis. In the present study, we demonstrate that cell death induced by suppression of PIN1 could be inhibited by ferrostatin-1 (Fer-1) and ferroptosis biomarkers including lactate dehydrogenase (LDH) release, lipid peroxidation and malondialdehyde (MDA) are upregulated by downregulating PIN1. We then discover that abrogation of PIN1 greatly decreases the level of glutathione peroxidase 4 (GPX4) and the level of PIN1 is positively correlated with the level of GPX4. Furthermore, the knockdown of PIN1 promotes ferroptosis induced by RSL3. The mechanism involves PIN1 silencing which downregulates GPX4 by decreasing the level of nuclear factor E2-related factor 2 (NRF2). Furthermore, overexpression of NRF2 inhibits RSL3-mediated ferroptosis of CC cells when PIN1 is silenced. In addition, our results indicate that cisplatin (DDP) induces ferroptosis, which is restrained by overexpression of PIN1. The PIN1 inhibitor, KPT-6566, promotes the cytotoxic effect of DDP. The present study reveals that PIN1 affects ferroptosis and sensitivity to DDP in CC cells via the NRF2/GPX4 axis, thereby identifying PIN1 as a potential therapeutic target for CC.

The Relationship of Redox With Hallmarks of Cancer: The Importance of Homeostasis and Context.

Redox homeostasis is a lifelong pursuit of cancer cells. Depending on the context, reactive oxygen species (ROS) exert paradoxical effects on cancers; an appropriate concentration stimulates tumorigenesis and supports the progression of cancer cells, while an excessive concentration leads to cell death. The upregulated antioxidant system in cancer cells limits ROS to a tumor-promoting level. In cancers, redox regulation interacts with tumor initiation, proliferation, metastasis, programmed cell death, autophagy, metabolic reprogramming, the tumor microenvironment, therapies, and therapeutic resistance to facilitate cancer development. This review discusses redox control and the major hallmarks of cancer.

SETD8 induces stemness and epithelial-mesenchymal transition of pancreatic cancer cells by regulating ROR1 expression.

Pancreatic cancer (PC) is one of the most deadly diseases, and its incidence is increasing year by year. The methyltransferase SETD8 has been demonstrated to play an important role in tumor cell proliferation and metastasis. However, little is known about whether SETD8 could affect the invasion and metastasis of PC and the mechanism underlying the regulation. Based on our previous report, here, we further found that SETD8 could promote the invasion and migration of PC cells by inducing the expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1). ROR1 was predominantly upregulated in PC tissues and was correlated with lymph node metastasis and worse prognosis. Mechanistically, SETD8 mediated ROR1 activity and regulated PC cells invasion and migration, although promoting the expression of stemness and epithelial-mesenchymal transition-related molecules. This promotion effect disappeared when the catalytically inactive mutant SETD8 was overexpressed, which could be counteracted by the SETD8-specific methyltransferase inhibitor UNC0379. Collectively, our results demonstrate that SETD8 may be a novel prognostic factor and a therapeutic target of PC.

MTAP Deficiency-Induced Metabolic Reprogramming Creates a Vulnerability to Cotargeting De Novo Purine Synthesis and Glycolysis in Pancreatic Cancer.

Methylthioadenosine phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20% to 30% of pancreatic cancer. Our previous study revealed that MTAP deficiency indicates a poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion-mediated metabolic reprogramming enhanced glycolysis and de novo purine synthesis in pancreatic cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF1α) protein via posttranslational phosphorylation. RIO kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF1α to regulate its stability. In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) and the de novo purine synthesis inhibitor l-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease. SIGNIFICANCE: This study demonstrates that MTAP status impacts glucose and purine metabolism, thus identifying multiple novel treatment options against MTAP-deficient pancreatic cancer.

FGFBP1-mediated crosstalk between fibroblasts and pancreatic cancer cells via FGF22/FGFR2 promotes invasion and metastasis of pancreatic cancer.

Fibroblast growth factor-binding protein 1 (FGFBP1) promotes fibroblast growth factor (FGF) activity by releasing FGFs from extracellular matrix storage. We previously reported that the tumor suppressor F-box and WD repeat domain-containing 7 suppresses FGFBP1 by reducing expression of c-Myc, which inhibits the proliferation and migration of pancreatic cancer cells. However, the potential mechanism by which FGFBP1 facilitates pancreatic ductal adenocarcinoma (PDAC) remains unexplored. In this study, we focused on the function of FGFBP1 in the interplay between cancer-associated fibroblasts (CAFs) and pancreatic cancer cells (PCCs). Decreased FGF22 expression was detected in CAFs co-cultured with PCCs with FGFBP1 abrogation, which was verified in the cell culture medium by enzyme-linked immunosorbent assay. Active cytokine FGF22 significantly facilitated the migration and invasion of PANC-1 and Mia PaCa-2 cells. The number of penetrating PCCs cocultured with CAFs with FGF22 abrogation was significantly less than that of the control group. Interestingly, higher expressions of FGF22 and fibroblast growth factor receptor 2 (FGFR2) were associated with worse prognosis of patients with PDAC and FGFR2, an independent prognostic marker of PDAC. The PANC-1 and Mia PaCa-2 cells with silenced FGFR2 showed weaker invasion and metastasis, even if these cells were simultaneously treated with cytokine FGF22. These results revealed that FGFBP1-mediated interaction between CAFs and PCCs via FGF22/FGFR2 facilitates the migration and invasion of PCCs. FGFR2 could act as a prognostic marker for patients with PDAC.

FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells.

FBW7 functions as a tumor suppressor by targeting oncoproteins for degradation. Our previous study found FBW7 was low expressed in pancreatic cancer due to sustained activation of Ras-Raf-MEK-ERK pathway, which destabilized FBW7 by phosphorylating at Thr205. MicroPET/CT imaging results revealed that FBW7 substantially decreased 18F-fluorodeoxyglucose uptake in xenograft tumors. Mechanistically, FBW7 inhibited glucose metabolism via c-Myc/TXNIP axis. But in these studies, we observed FBW7 down-regulated genes were widely involved in redox reaction and lipid metabolism. Here we reanalyzed previous gene expression profiling and conducted targeted cell metabolites analysis. Results revealed that FBW7 regulated lipid peroxidation and promoted ferroptosis, a non-apoptotic form of cell death. Mechanistically, we found FBW7 inhibited the expression of stearoyl-CoA desaturase (SCD1) via inhibiting nuclear receptor subfamily 4 group A member 1 (NR4A1). SCD1 was reported to inhibit both ferroptosis and apoptosis, which was consistent with the function of FBW7 and NR4A1, another FBW7 down-regulated gene in the gene expression profiling. Moreover, FBW7 potentiated cytotoxic effect of gemcitabine via activating ferroptosis and apoptosis. Combination ferroptosis inducers and apoptosis activators could also significantly potentiated cytotoxic effect of gemcitabine in pancreatic cancer. Therefore, our findings might provide new strategies for the comprehensive treatment of pancreatic cancer.

SETD8 potentiates constitutive ERK1/2 activation via epigenetically silencing DUSP10 expression in pancreatic cancer.

Constitutive ERK1/2 activation has been frequently observed in pancreatic adenocarcinoma (PDAC). How ERK1/2 activation status been potentiated and maintained by epigenetic mechanisms has seldom been discussed in PDAC. In this study, we first examined the expression status of p-ERK1/2 in PDAC tissues by immunohistochemical staining and then screened possible epigenetic factors that displayed different expression status between p-ERK1/2 high and low groups by RNA profiling, and found that SETD8 displayed an increased expressional pattern in p-ERK1/2high patient group. Then the impact of SETD8 on the proliferation of PDAC cells were investigated on the basis of gain or loss-of-function assays. RNA sequencing assays were performed to screen potential SETD8 downstream targets that contribute to ERK1/2 activation. Mass spectrometry and transcriptional analysis, including dual-luciferase assay and chromatin immunoprecipitation assay (ChIP), were used to explore the molecular mechanisms that governing SETD8-mediated ERK1/2 activation. In vitro cell line studies and in vivo xenograft mouse model studies indicated that SETD8 promoted cell proliferation and increased tumor formation capacity of PDAC cell lines. Mechanism explorations uncovered that SETD8 suppressed the expression of DUSP10, which was responsible for dephosphorylation of ERK1/2. Mass spectrometry and transcriptional analysis results demonstrated that STAT3 interacted with SETD8 and recruited SETD8 to the promoter region of DUSP10, leading to epigenetic silencing of DUSP10 and the resultant activation of ERK1/2. In conclusion, SETD8 interacts with STAT3 on DUSP10 promoter region and epigenetically silences DUSP10 expression. Decreased DUSP10 expression in PDAC potentiates activation of ERK1/2 phosphorylation, resulting in unfavorable prognosis of PDAC.

Oncogenic function of TRIM2 in pancreatic cancer by activating ROS-related NRF2/ITGB7/FAK axis.

Evidence suggests that tripartite motif-containing 2 (TRIM2) is associated with carcinogenic effects in several malignancies. However, the expression patterns and roles of TRIM2 in pancreatic cancer are rarely studied. Our study demonstrated that TRIM2 was expressed in a high percentage of pancreatic tumors. High TRIM2 expression was negatively correlated with the outcome of pancreatic cancer. TRIM2 silencing significantly inhibited the proliferation, migration, invasion, and in vivo tumorigenicity of pancreatic cancer cells. Regarding the mechanism involved, TRIM2 activated ROS-related E2-related factor 2 (NRF2)/antioxidant response element (ARE) signaling and the integrin/focal adhesion kinase (FAK) pathway. Treatment of pancreatic cancer cells with the antioxidant N-acetyl-L-cysteine decreased ROS activity and expression level of NRF2 and ITGB7. Increased translocation of NRF2 protein into nucleus further rescued the inhibited ITGB7 transcription. Moreover, NRF2 bound to the potential ARE on the promoter region and enhanced the transcriptional activity of ITGB7, indicating the bridging effect of NRF2 between the two signaling pathways. In summary, our study provides evidence that upregulated TRIM2 in pancreatic cancer predicts short survival for pancreatic cancer patients. TRIM2 accelerates pancreatic cancer progression via the ROS-related NRF2/ITGB7/FAK axis.

Function and regulation of F-box/WD repeat-containing protein 7.

The ubiquitin-proteasome system is an important post-translational modification system involved in numerous biological processes, such as cell cycle regulation, gene transcription, signal transduction, apoptosis, differentiation and development. F-box/WD repeat-containing protein 7 (FBXW7) is one of the most studied F-box (FBX) proteins, serving as substrate recognition component of S phase kinase-associated protein 1-Cullin 1-FBX protein complexes. As a tumor suppressor, FBXW7 recognizes numerous proto-oncoproteins and promotes their ubiquitination and subsequent proteasomal degradation. FBXW7 is regulated at different levels, leading to tunable and specific control of the activity and abundance of its substrates. Therefore, genetic mutations or decreases in its expression serve an important biological role in tumor development. In-depth studies and identification of additional substrates targeted by FBXW7 have suggested a signaling network regulated by FBXW7, including its tumor-inhibitory role. The present review focused on the role of FBXW7 in tumor suppression and its application in cancer therapy.

Abrogation of ARF6 promotes RSL3-induced ferroptosis and mitigates gemcitabine resistance in pancreatic cancer cells.

ADP Ribosylation Factor 6 (ARF6) is a part of the RAS superfamily and regulates vesicular trafficking, remodeling of membrane lipids, and signaling pathways. Our previous study has found that ARF6, functioned as a downstream of Kras/ERK signaling pathway, could promote proliferation and Warburg effect in pancreatic cancer cells. Moreover, ARF6 is promising to be a biomarker for predicting prognosis of pancreatic cancer. Ferroptosis is a new defined iron-dependent form of nonapoptotic cell death, which is closely related to Kras mutation. Therefore, it is urgent to further explore the relationship between ARF6 and ferroptosis. Our study demonstrated that ARF6 did not directly regulate lipid peroxidation, but endowed pancreatic cancer cells to a status that is sensitive to oxidative stress, especially RSL3-induced lipid peroxidation. Further study revealed that ARF6 could also regulate gemcitabine resistance via multiple pathways. In conclusion, ARF6 has a profound effect on pancreatic cancer development.

Pin1 promotes pancreatic cancer progression and metastasis by activation of NF-κB-IL-18 feedback loop.

OBJECTIVES: Accumulated evidence suggests that Pin1 contributes to oncogenesis of diverse cancers. However, the underlying mechanism of oncogenic function of Pin1 in PDAC requires further exploration. MATERIALS AND METHODS: IHC was performed using PDAC tissues. Western blot, PCR, immunofluorescence and transwell were performed using cell lines. GSEA were applied for possible downstream pathways. ChIP assay and dual luciferase were used for assessment of transcriptional activity. RESULTS: Both Pin1 and IL-18 levels are increased in primary PDAC tissues and that their levels are positively correlated. High expression of IL-18 is a predictor of poor prognoses. Pin1 promoted pancreatic cancer cell proliferation and motility by increasing IL-18 expression, while Pin1 knockdown also inhibited the tumour-promoting effect of IL-18. Both Pin1 and IL-18 could enhance the NFκB activity in pancreatic cancer cells. When bound to the p65 protein, Pin1 promoted p65 phosphorylation and its nuclear translocation. In the nucleus, Pin1 and p65 simultaneously bound to the IL-18 promoter and enhanced IL-18 transcription. In addition, recruitment of p65 to the IL-18 promoter was decreased in Pin1-silenced cells. CONCLUSIONS: Our study improves the understanding of Pin1 in tumour-promoting inflammation in PDAC, which is a hallmark of cancer; Pin1 interacted with p65 in PDAC and enhanced NF-κB signalling and downstream transcriptional activation of IL-18, with increased IL-18 continuously activating NF-κB signalling, which then forms a positive feedback loop.

Prognostic Value and Clinical Predictors of Lymph Node Metastases in Pancreatic Neuroendocrine Tumors.

OBJECTIVES: To investigate the correlation between lymph node metastasis (LNM) and various clinicopathological features of pancreatic neuroendocrine tumors (pNETs) and its impact on prognosis. METHODS: We searched the Surveillance Epidemiology and End Results database (2004-2015) for patients with surgically treated pNETs. Factors correlated with LNMs were analyzed by logistic regression and by Cox analysis. RESULTS: For tumors of 1 to 4 cm, age (P < 0.001, P = 0.014), grade (P < 0.001, P < 0.001), LNMs (P = 0.008, P < 0.001), and size (P = 0.038, P = 0.002) predicted overall survival (OS) and disease-specific survival (DSS). For tumor greater than 4 cm, age (P < 0.001, P = 0.001) and grade (P = 0.011, P = 0.048) were independent prognostic factors of OS and DSS. Lymph node metastasis modestly predicted DSS (P = 0.028) but not OS (P = 0.218). CONCLUSIONS: In pNETs greater than 4 cm, LNM is not a predictor of OS and modestly predicts DSS, and lymphadenectomy may be unhelpful in these patients. For pNETs 1 to 4 cm, LNM predicts poor OS and DSS, which supports lymphadenectomy in these patients. Pancreas-sparing resection with only limited peripancreatic node sampling needs to be questioned.

Ferroptosis: Final destination for cancer?

Ferroptosis is a recently defined, non-apoptotic, regulated cell death (RCD) process that comprises abnormal metabolism of cellular lipid oxides catalysed by iron ions or iron-containing enzymes. In this process, a variety of inducers destroy the cell redox balance and produce a large number of lipid peroxidation products, eventually triggering cell death. However, in terms of morphology, biochemistry and genetics, ferroptosis is quite different from apoptosis, necrosis, autophagy-dependent cell death and other RCD processes. A growing number of studies suggest that the relationship between ferroptosis and cancer is extremely complicated and that ferroptosis promises to be a novel approach for the cancer treatment. This article primarily focuses on the mechanism of ferroptosis and discusses the potential application of ferroptosis in cancer therapy.

Management of solid pseudopapillary neoplasms of pancreas: A single center experience of 243 consecutive patients.

BACKGROUND: Solid pseudopapillary neoplasm of the pancreas (SPN) is a rare neoplasm, which mainly affects young women. The aim of this study was to investigate the clinicopathological features and surgical management of SPNs in our institution. METHODS: Patients who underwent surgery for a pathologically confirmed SPN in our institution between January 2008 and October 2018 were collected. Their clinical characteristics and survival associations were analyzed. RESULTS: In total, 243 pathologically confirmed patients were analyzed in this study, including 181(74.5%)females and 62(25.5%) males. The mean age was 35.3 years old (range: 12-64 years old) with average tumor size of 4.83 cm (range: 0.8-16 cm). 239 patients underwent complete surgical resection. After median follow-up of 46 months (range: 10-118 months), four patients died due to tumor progression. All the other people were absent of local recurrence or distant metastasis. CONCLUSIONS: SPN is a latent malignant tumor with excellent prognosis. Surgical resection is recommended even in the presence of liver metastasis. If possible, function-preserving surgery is advocated. High Ki67 index may predict the malignant potential and poor prognosis of SPNs.

Laparoscopic pancreaticoduodenectomy: are the best times coming?

BACKGROUND: The introduction of laparoscopic technology has greatly promoted the development of surgery, and the trend of minimally invasive surgery is becoming more and more obvious. However, there is no consensus as to whether laparoscopic pancreaticoduodenectomy (LPD) should be performed routinely. MAIN BODY: We summarized the development of laparoscopic pancreaticoduodenectomy (LPD) in recent years by comparing with open pancreaticoduodenectomy (OPD) and robotic pancreaticoduodenectomy (RPD) and evaluated its feasibility, perioperative, and long-term outcomes including operation time, length of hospital stay, estimated blood loss, and overall survival. Then, several relevant issues and challenges were discussed in depth. CONCLUSION: The perioperative and long-term outcomes of LPD are no worse and even better in length of hospital stay and estimated blood loss than OPD and RPD except for a few reports. Though with strict control of indications, standardized training, and learning, ensuring safety and reducing cost are still and will always the keys to the healthy development of LPD; the best times for it are coming.