Targeting Cancer- and Chemotherapy-Induced Anorexia and Cachexia using the GDF15/GFRAL Signalling System

Abstract

Anorexia/cachexia syndrome (ACS) causes the mortality of 20-30% of cancer patients and worsens the prognosis of many more. The mechanisms underlying ACS are poorly understood and, therefore, there is currently no effective method to combat this condition. Growth differentiation factor 15 (GDF15) is a cytokine which is released in response to cell stress and damage, such as is caused by cancer and chemotherapy. The action of GDF15 on its cognate receptor, GDNF alpha-like receptor (GFRAL), has been linked to anorexia, cachexia and nausea. The GDF15/GFRAL signalling network may therefore be a good target for cancer- and chemotherapy-induced ACS. In this thesis, I demonstrated that a low dose of exogenous GDF15 caused anorexia and aversion in healthy mice and pica behaviour in rats. Immunohistochemistry (IHC) showed that this low dose of GDF15 caused activation of neurons in the dorsal vagal complex (DVC), the lateral parabrachial nucleus, the central amygdala, the paraventricular nucleus of the hypothalamus, and the oval nucleus of the bed nucleus of the stria terminalis. These areas are known to be involved in signalling anorexia and weight loss. Retrograde tracing showed connections between activated neurons in these areas. Furthermore, IHC illuminated different neuronal phenotypes activated by GDF15 in these areas, including neurons containing the neuropeptide, cholecystokinin (CCK), in the DVC. Signalling through this population and the consequent anorexia was prevented pharmacologically using a CCK receptor antagonist or by selectively ablating these CCK neurons genetically. In future, it will be possible to directly manipulate GFRAL neurons using our bespoke Gfral-Cre mouse model, which I validated in my thesis. Gfral-Cre mice were crossed with a fluorescent reporter strain to show fidelity of Cre expression in GFRAL neurons. The mice were also crossed with a 1TB-hM3DqmCherry mouse, which caused the selective expression of a designer receptor, the activation of which caused anorexia and prevented gastric emptying. GFRALDVC neurons were activated by GDF15, but not by other satiety or sickness signals. GFRAL neurons were, however, activated by chemotherapy treatments which caused anorexia, weight loss, and the increase of GDF15 in otherwise healthy mice. For these chemotherapy treatments, the prevention of GFRAL signalling by congenital knock out of the GFRAL receptor, or by treatment with a GFRAL-blocking antibody, reduced or reversed anorexia and weight loss. Although three different murine cancer models were tested here, none showed a suitable ACS phenotype which would have allowed further study of the link between GDF15 and cancer ACS. The effects of GDF15/GFRAL signalling during chemotherapy in this thesis, and reported during cancer in other literature, show the GDF15/GFRAL signalling network to be a promising target to combat ACS in cancer and chemotherapy.

Date of Award	31 Dec 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Caroline Springer (Supervisor), Simon Luckman (Supervisor) & Jamie Honeychurch (Supervisor)