1652P - Interaction between enhanced cytokine signalling and ferroptosis defence fuels obesity-associated pancreatic ductal adenocarcinoma oncogenesis

Background

Obesity amplifies the risk for various cancers, including pancreatic cancer (PC). Due to limited early screening methods, this study seeks to investigate the effects of obesity-related metabolic disorders on PC initiation and offer novel insights into early detection and diagnosis in obese populations.

Methods

Human pancreatic Nestin-expressing ductal cells (HPNE) were cultured with human serum obtained from obese patients and healthy individuals. Transcriptomics, untargeted metabolomics, and joint-pathway analyses were conducted to examine the impacts of obesity-related metabolic disorders on pancreatic carcinogenesis. Multiomics analysis results were validated using cells of varying genetic backgrounds, while their mechanisms and roles in PDAC development were explored in obese transgenic mouse models. Clinical relevance and translational value were also corroborated using public databases and human samples.

Results

Multiomic assessment revealed heightened cytokine signalling and ferroptosis defence in HPNE cells exposed to obesity serum. In vitro tests showed that upregulated interleukin 34 (IL-34) strengthens ferroptosis defence through oxidative stress, while the enhanced ferroptosis defence reciprocally raises IL-34 levels. Our study demonstrated that augmented IL-34 signalling and ferroptosis defence hasten PDAC initiation in diet-induced obese mice by increasing immunosuppressive macrophages infiltration. Public databases revealed a strong correlation between elevated IL-34 and glutathione peroxidase 4 (GPX4) expression in pancreatic tumors vs. normal tissues. Gene signature expression displayed substantial correlations as well. Cohort validation and single-cell analysis suggested a positive association between IL-34 signalling and ferroptosis defence enhancement with PDAC patients' body mass index (BMI).

Conclusions

Obesity elevates IL-34 signalling and ferroptosis defence, thereby promoting PDAC development via macrophage-induced immunosuppression. The observed positive correlations between IL-34 and BMI, as well as GPX4 and BMI in PDAC patients underscore their potential roles in early PC screening among the obese population.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

This project received funding from the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1-002), National High Level Hospital Clinical Research Funding (2022-PUMCH-D-001), National Multidisciplinary Cooperative Diagnosis and Treatment Capacity Building Project for Major Diseases, National Natural Science Foundation of China (NSFC, 81970763), Foundation Project for Young Scientists of NSFC (82102810), the Fellowship of China Postdoctoral Science Foundation (2021M700501), the Postdoctoral ScienceFoundation of Peking Union Medical College Hospital (2022T150067), and the Non-profit Central Research Institute Fund of CAMS (2018PT32014).

Disclosure

All authors have declared no conflicts of interest.