Oral Presentation ESA-SRB-AOTA 2019

Interrogating Bone Morphogenetic Signalling in cancer cachexia (#33)

Adam Hagg 1 2 , Roberta Sartori 3 , Craig A Harrison 1 , Marco Sandri 3 , Paul Gregorevic 2
  1. Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, Victoria, Australia
  2. Physiology, University of Melbourne, Melbourne, Victoria, Australia
  3. Department of Biomedical Sciences, University of Padova, Padova, Italy

Cancer cachexia is characterised by debilitating frailty and fatigue associated with profound loss of lean and fat mass. Complications arising from cachexia increase morbidity, reducing patients’ quality of life, and ultimately account for 1 in 3 advanced cancer deaths. Loss of muscle mass associated with cachexia is a key prognostic indicator in the clinic, and pre-clinical studies have shown that preservation of muscle mass extends the lifespan of cachectic mice independent of tumor progression. The mechanisms underlying cachexia remain incompletely defined.

Recent studies have established that Bone Morphogenetic Protein (BMP) signalling is a key regulator of skeletal muscle plasticity. We sought to investigate the contribution of the BMP pathway to the cachectic phenotype in mice.

In the muscles of multiple cachectic mouse models, we observed diminished Smad1/5/8 phosphorylation (a key BMP effector), and increased expression of the BMP antagonist Noggin. Increasing Noggin expression in the muscles of tumor-free mice resulted in muscle atrophy resembling cachexia. Expression of Interleukin-6 (IL-6) was sufficient to induce Noggin gene expression in cancer-free mice and genetic inhibition of IL-6 signalling reduced Noggin gene expression in tumor-bearing mice.

Seeking to evaluate the therapeutic potential of modulating the BMP pathway, we observed that genetic and pharmacological interventions to increase BMP signalling reduced muscle wasting associated with tumor burden in mice and extended lifespan by over 50%.

As the BMP pathway is a regulator of neuromuscular junction formation in insects, we investigated whether impaired BMP-Smad1/5/8 signalling in cachectic muscles is associated with remodeling of the neuromuscular junction. Our studies revealed that significant neuromuscular junction defects arise with cachexia progression.  

Our studies demonstrate a novel role of perturbed BMP signalling in the pathogenesis underlying cancer cachexia, and support further investigation of interventions targeting the BMP pathway as potential treatments.