The prognosis for the most common type of pancreatic cancer, pancreatic ductal adenocarcinoma, also known as PDAC, remains poor. Only around 4% of PDAC patients are likely to live 5 years after being diagnosed. The immune system plays a part in the progression of PDAC, as increased inflammation contributes to the growth of the tumour and its ability to resist treatment.
The NF-κB proteins of the immune system are transcription factors that control when and how much certain other proteins are produced. The protein RELA is an important member of the NF-κB family. It is known to be overactivated in PDAC tumours and may be responsible for the high levels of inflammation found in this type of pancreatic cancer. A better understanding of how RELA is activated in PDAC cells will help develop medicines targeting this process.
Butera et al. combined experimental and computational approaches to model a network of interactions between key molecules in lines of human PDAC cells grown in the laboratory to investigate how RELA is controlled. Usually, when the RELA protein is activated, it is located in the cell’s nucleus, this means that tracking the location of RELA within the cell can reveal its activated form. To follow RELA, it was labelled with a fluorescent marker and visualised using live, high-throughput fluorescence microscopy.
When RELA was activated with a pro-inflammatory molecule TNFα, it changed how it moved in and out of the cell’s nucleus. Using computational modelling approaches, Butera et al. could build a statistical model that revealed that the location and activity of RELA is affected by actin, a key component of the cell’s molecular scaffolding called the cytoskeleton.
When actin was disrupted, RELA's activity was altered. Moreover, profiling targets of RELA using RNA sequencing revealed two genes that encode proteins related to the regulation of actin. This indicates that RELA activity – which is itself affected by actin organisation – can feed back to regulate actin.
Butera et al. have identified genes regulated by RELA in PDAC cells that could be used as targets for anti-cancer drug development. Further research into the feedback between RELA and actin will help untangle the complex network that causes inflammation in pancreatic cancer.