Microbiota is just beginning to be recognized as an important player in carcinogenesis and the interplay among microbes is greater than expected. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for which mortality closely parallels incidence. Early detection would provide the best opportunity to increase survival rates. Specific well-studied oral, gastrointestinal, and intrapancreatic microbes and some kinds of hepatotropic viruses and bactibilia may have potential etiological roles in pancreatic carcinogenesis, or modulating individual responses to oncotherapy. Concrete mechanisms mainly involve perpetuating inflammation, regulating the immune system-microbe-tumor axis, affecting metabolism, and altering the tumor microenvironment. The revolutionary technology of omics has generated insight into cancer microbiomes. A better understanding of the microbiota in PDAC might lead to the establishment of screening or early-stage diagnosis methods, implementation of cancer bacteriotherapy, adjustment of therapeutic efficacy even alleviating the adverse effects, creating new opportunities and fostering hope for desperate PDAC patients.

The overall five-year survival rate of pancreatic cancer has hardly changed in the past few decades (less than 10%) because of resistance to all known therapies, including chemotherapeutic drugs. In the past few decades, gemcitabine has been at the forefront of treatment for pancreatic ductal adenocarcinoma, but more strategies to combat drug resistance need to be explored. One promising possibility is ferroptosis, a form of a nonapoptotic cell death that depends on intracellular iron and occurs through the accumulation of lipid reactive oxygen species, which are significant in drug resistance. In this article, we reviewed gemcitabine-resistance mechanisms; assessed the relationship among ferroptosis, tumorigenesis and gemcitabine resistance, and explored a new treatment method for pancreatic cancer.

Damaged DNA-binding protein 1 (DDB1) recruits nucleotide excision pathway proteins to form the UV-damaged DNA-binding protein complex and is required for DNA repair. DDB1 was reported to participate in apoptosis and chemoresistance regulation in several cancers. However, little is known about the function of DDB1 in pancreatic adenocarcinoma (PDAC). In this study, we reported that DDB1 functions as a tumor-promoting factor in PDAC by regulating cancer cell proliferation, epithelial-mesenchymal transition (EMT) and chemoresistance. Compared to normal pancreatic tissues, PDAC tissues had high expression levels of DDB1, and this high expression was positively correlated with poor prognosis. Furthermore, reductions in cell proliferation and EMT were observed in DDB1-deficient PDAC cell lines. Intriguingly, we also found that abrogation of DDB1 expression increased PDAC cell sensitivity to gemcitabine (GEM). Mechanistically, DDB1 knockdown was associated with an increase in deoxycytidine kinase expression in vivo and in vitro. In summary, our work demonstrated that DDB1 promotes PDAC progression and chemoresistance and may serve as a potential predictive marker and therapeutic target for PDAC treatment.

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.

Pancreatic cancer is an aggressive malignancy with high mortality rates and poor prognoses. Despite rapid progress in the diagnosis and treatment of pancreatic cancer, the efficacy of current therapeutic strategies remains limited. Hence, better alternative therapeutic options for treating pancreatic cancer need to be urgently explored. Mesenchymal stromal cells (MSCs) have recently received much attention as a potential therapy for pancreatic cancer owing to their tumor-homing properties. However, the specific antitumor effect of MSCs is still controversial. To this end, we aimed to focus on the potential anti-cancer treatment prospects of the MSC-based approach and summarize current challenges in the clinical application of MSCs to treat pancreatic cancer.