Metabolic reprogramming of cancer-associated fibroblasts in pancreatic cancer contributes to the intratumor heterogeneity of PET-CT.

Intratumor heterogeneity of positron emission tomography-computed tomography (PET-CT) is reflected by variable 18F-fluorodeoxyglucose (FDG) uptake. Increasing evidence has shown that neoplastic and non-neoplastic components can affect the total 18F-FDG uptake in tumors. Cancer-associated fibroblasts (CAFs) is considered as the main non-neoplastic components in tumor microenvironment (TME) of pancreatic cancer. Our study aims to explore the impact of metabolic changes in CAFs on heterogeneity of PET-CT. A total of 126 patients with pancreatic cancer underwent PET-CT and endoscopic ultrasound elastography (EUS-EG) before treatment. High maximum standardized uptake value (SUVmax) from the PET-CT was positively correlated with the EUS-derived strain ratio (SR) and indicated poor prognosis of patients. In addition, single-cell RNA analysis showed that CAV1 affected glycolytic activity and correlated with glycolytic enzyme expression in fibroblasts in pancreatic cancer. We also observed the negative correlation between CAV1 and glycolytic enzyme expression in the tumor stroma by using immunohistochemistry (IHC) assay in the SUVmax-high and SUVmax-low groups of pancreatic cancer patients. Additionally, CAFs with high glycolytic activity contributed to pancreatic cancer cell migration, and blocking CAF glycolysis reversed this process, suggesting that glycolytic CAFs promote malignant biological behavior in pancreatic cancer. In summary, our research demonstrated that the metabolic reprogramming of CAFs affects total 18F-FDG uptake in tumors. Thus, an increase in glycolytic CAFs with decreased CAV1 expression promotes tumor progression, and high SUVmax may be a marker for therapy targeting the neoplastic stroma. Further studies should clarify the underlying mechanisms.

Cuproptosis-Related Gene DLAT as a Novel Biomarker Correlated with Prognosis, Chemoresistance, and Immune Infiltration in Pancreatic Adenocarcinoma: A Preliminary Study Based on Bioinformatics Analysis.

A novel form of cell death, cuproptosis, was recently identified to be mediated by the binding of copper to lipoylated enzymes of the tricarboxylic acid cycle. Cuproptosis-related genes (CRGs) may play a crucial role in the progression of pancreatic adenocarcinoma (PAAD), which often exhibits metabolic reprogramming. In the present study, univariate Cox regression analysis and Kaplan-Meier survival analysis were performed to identify prognostic CRGs. Data from the Cancer Therapeutics Response Portal and the Genomics of Drug Sensitivity in Cancer database were downloaded for drug sensitivity analysis. DLAT was identified as the only prognostic CRG in PAAD (HR = 2.72; 95% CI, 1.10-6.74). Functional enrichment analyses indicated that the basic function of DLAT is closely related to metabolism, and multiple tumor-promoting and immune response-related pathways were enriched in DLAT-high PAAD samples. The influence of DLAT and related genes on cancer immunity was evaluated by comprehensive immune infiltration analyses, which revealed the value of these genes as biomarkers for evaluating the sensitivity to immunotherapy. Additionally, high DLAT expression induced drug resistance, and significantly increased resistance to commonly used chemotherapeutics in PAAD, such as gemcitabine, oxaliplatin, 5-fluorouracil, and irinotecan. In conclusion, our study preliminarily revealed the prognostic value of DLAT, which is correlated with PAAD progression, chemoresistance, and immune infiltration, providing a valuable reference for PAAD treatment. However, our findings need to be confirmed by further in vivo and in vitro experiments.

Signaling pathways in cancer-associated fibroblasts: recent advances and future perspectives.

As a critical component of the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well-known signaling pathways, including the transforming growth factor-ß (TGF-ß), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa-B (NF-κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT pathways, as well as transcription factors, including hypoxia-inducible factor (HIF), heat shock transcription factor 1 (HSF1), P53, Snail, and Twist, constitute complex regulatory networks in the TME to modulate the formation, activation, heterogeneity, metabolic characteristics and malignant phenotype of CAFs. Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics, and this modulation partially depends on the regulation of signaling cascades. The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures (e.g., NCT01130142 and NCT01064622). Hence, a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma-targeted cancer therapies. Here, we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

Prognostic value of circulating tumor DNA in pancreatic cancer: a systematic review and meta-analysis.

Increasing evidence has revealed the potential correlation between circulating tumor DNA (ctDNA) and the prognosis of pancreatic cancer, but inconsistent findings have been reported. Therefore, a meta-analysis was performed to evaluate the prognostic value of ctDNA in pancreatic cancer. The Embase, MEDLINE, and Web of Science databases were searched for relevant articles published until April 2020. Articles reporting the correlation between ctDNA and the prognosis of pancreatic cancer were identified through database searches. The pooled hazard ratios (HRs) for prognostic data were calculated and analyzed using Stata software. A total of 2326 patients pooled from 25 eligible studies were included in the meta-analysis to evaluate the prognostic value of ctDNA in pancreatic cancer. Patients with mutations detected or high concentrations of ctDNA had a significantly poorer overall survival (OS) (univariate: HR = 2.54; 95% CI, 2.05-3.14; multivariate: HR = 2.07; 95% CI, 1.69-2.54) and progression-free survival (PFS) (univariate: HR = 2.18; 95% CI, 1.41-3.37; multivariate: HR = 2.20; 95% CI, 1.38-3.52). In conclusion, the present meta-analysis indicates that mutations detected or high concentrations of ctDNA are significant predictors of OS and PFS in patients with pancreatic cancer.

The promising role of noncoding RNAs in cancer-associated fibroblasts: an overview of current status and future perspectives.

As the most important component of the stromal cell population in the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) are crucial players in tumor initiation and progression. The interaction between CAFs and tumor cells, as well as the resulting effect, is much greater than initially expected. Numerous studies have shown that noncoding RNAs (ncRNAs) play an irreplaceable role in this interplay, and related evidence continues to emerge and advance. Under the action of ncRNAs, normal fibroblasts are directly or indirectly activated into CAFs, and their metabolic characteristics are changed; thus, CAFs can more effectively promote tumor progression. Moreover, via ncRNAs, activated CAFs can affect the gene expression and secretory characteristics of cells, alter the TME and enhance malignant biological processes in tumor cells to contribute to tumor promotion. Previously, ncRNA dysregulation was considered the main mechanism by which ncRNAs participate in the crosstalk between CAFs and tumor cells. Recently, however, exosomes containing ncRNAs have been identified as another vital mode of interaction between these two types of cells, with a more direct and clear function. Gaining an in-depth understanding of ncRNAs in CAFs and the complex regulatory network connecting CAFs with tumor cells might help us to establish more effective and safer approaches for cancer therapies targeting ncRNAs and CAFs and offer new hope for cancer patients.