Effect of a high fat diet on macrophage function and liver metastasis

Context. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. It commonly spreads to the liver, through a process known as metastasis and this is the primary cause of death for those with PDAC. Thus, there is an urgent need to prevent pancreatic cancer reaching the liver. Progress is hindered by lack of a detailed understanding of the mechanisms that cause the aggressive metastatic nature of PDAC. Our team has shown that PDAC liver metastasis is influenced by non-cancerous cells supporting the seeding and growth of cancer cells at the distant site. PDAC liver metastatic tumours are often invaded by a type of white blood cells called macrophages. Macrophages are a key part of our immune system and are present in all tissues. In cancer, macrophages can either prevent or promote metastasis depending on their activation state. Approaches that aim to manipulate macrophages to prevent metastatic spreading represent an attractive treatment strategy for PDAC. A particular property of macrophages is to clear dead cells to maintain homeostasis by a process called efferocytosis. Efferocytosis is actively anti-inflammatory to prevent tissue damage. Last year, our team found that in the context of pancreatic cancer, the anti-inflammatory features of macrophages carrying out efferocytosis prevent an anti-tumour immune response and support liver metastasis. Thus, targeting efferocytosis could potentially be beneficial for the treatment of cancer. Challenges. In 2025, there is a widespread overconsumption of dietary fat, resulting in around 32% of the world population having dietary-induced liver steatosis, characterised by fats building up inside liver cells (hepatocytes). Population wide studies looking at the frequency of cancers and metastasis show that people with liver steatosis are at higher risk of developing liver metastasis, suggesting that steatotic livers provide a fertile ground for disseminated cancer cells. Our new data show that mice with liver steatosis are more susceptible to develop pancreatic cancer liver metastasis. Importantly, inhibition of efferocytosis in steatotic livers reduces liver metastasis, suggesting a molecular link between dietary induced liver steatosis, efferocytosis, and PDAC liver metastasis. However, the precise molecular mechanisms by which liver steatosis supports PDAC liver metastasis remain unknown. It is this knowledge gap that we aim to address here. Hypothesis and Aims. Our central hypothesis is that a high fat diet reprogrammes liver macrophage functions towards supporting metastasis, thereby promoting metastatic PDAC tumour growth in steatotic livers. We will address this hypothesis with the following specific aims: Investigate the effect of a high fat diet on pancreatic cancer metastasis. Identify molecular targets regulating dietary-induced reprogramming of macrophages. Target dietary-induced reprogrammed macrophages to stop liver metastasis. Potential applications and benefits. This project will reveal fundamental insights into how in pancreatic cancer, an unhealthy high fat diet can have detrimental effects on metastatic disease initiation and progression by reprogramming liver macrophages to support liver metastasis. This study will provide the rationale for developing better treatments for pancreatic cancer. We are ideally positioned to translate our science into new therapies through our close collaboration with the clinical teams at the Centre for Experimental Cancer Medicine, Clatterbridge Cancer Centre and Liverpool Royal University Hospital. This work will also have applications for other cancer types spreading to the liver and non-cancerous liver diseases linked to liver damage.