Poster Presentation 4th Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity Meeting 2024

Ablation of GFRAL neurons improves cachexia and reduces cancer burden in a mouse model of pancreatic cancer (#174)

Yunpeng Liu 1 , Abigail Wust 1 , Nikita Bajaj 1 , Sarah H Lockie 1
  1. Physiology, Monash Biomedicine Discovery Institute, Clayton, Victoria, Australia

Background:

Cachexia is a metabolic syndrome caused by chronic illnesses. Approximately 50% of cancer patients experience cachexia, and it contributes to approximately 30% of cancer-related deaths. Cachexia leads to fatigue, weight loss, and reduced food consumption, which, in turn, decreases patients' tolerance to treatments. Currently, there is no known treatment that can completely reverse these symptoms. Growth/differentiation factor-15 (GDF15) is a stress-related cytokine that exhibits relatively high levels in patients with chronic illnesses, including cancer, and is involved in body weight regulation. The receptor for GDF15 is GDNF family receptor α-like (GFRAL), which is expressed in a small population of neurons in the hindbrain. This suggests a potential role for GFRAL-expressing neurons in regulation of metabolic control in cancer cachexia.

Aim:

To investigate how the ablation of GFRAL neurons changes metabolic and appetite regulation a mouse model of cancer cachexia.

Method:

We used mice expressing diphtheria toxin (DT) receptors exclusively in GFRAL-containing neurons using the Cre-Lox system, allowing for the targeted killing of GFRAL neurons with DT via IP injection. To model pancreatic cancer, mice lacking GFRAL neurons and their intact littermates received an IP injection of pancreatic ductal adenocarcinoma (PDAC) cells derived from C57BL/6 KRASG12D P53R172H Pdx-Cre+/+ (KPC) mice. These mice subsequently developed pancreatic cancer, and associated cachexia.

Results:

Over 14 days of pancreatic cancer, mice lacking GFRAL neurons ate significantly more food, and lost significantly less body weight than WT littermates. These effects were more pronounced in male mice, with female sex being somewhat protective in WT mice.  

In the mice lacking GFRAL neurons, there was reduced tumour burden. Compared to WT mice, these mice developed significantly smaller tumours. There was a strong positive correlation between both food intake and body weight, and tumour size, suggesting the protective effects of GFRAL loss are driven by smaller tumour size in these mice.

Conclusion:

  • The ablation of GFRAL neurons improves cachexia outcomes in a mouse model of pancreatic cancer
  • The ablation of GFRAL neurons improves food intake in tumour-bearing mice.
  • Effects on cachexia symptoms may be due to reduced tumour burden, rather than direct effects on whole body metabolism.
  • Potentially, tumour development is restrained by ablation of GFRAL neurons, which suggests novel tumour growth signalling pathway.