Boast and Toast Submission
Name:
Graham Robertson
Member Group:
Kinghorn/Garvan
Project/Program title:
Cancer cachexia and tumorkines
Research achievement/milestone to boast:
Publication of paper in Cell Metabolism (IF 17.5). Petruzzelli M, Schwieger M, Schreiber R, Campos-Olivas R,
Tsoli M, Allen J, Swarbrick M, Rose-John S, Rincon M,Graham Robertson, Zechner R, Wagner EF. A switch from
white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metabolism 20:1-15.
http:dx.doi.org/10.1016/j.cmet.2014.06.011.
Due to the intense interest in brown fat in human health as beneficial for diabetes and obesity, this paper was
subject of a commentary in Science, as it explored how in the converse setting of cancer cachexia, brown fat is
detrimental.
Invited oral presentation at 2nd Cancer Cachexia conference, Montreal Sept 2014 - "Thermogenesis and altered
lipid metabolism in cancer cachexia".
Significance to overall research project/program/member/member group: This paper continues the work of
my group to understand the metabolic aberrations associated with cancer cachexia. We previously showed
that activation of heat generation in brown adipose tissue (BAT) of cachectic tumour-bearing mice represents
excessive energy expenditure (Tsoli M et al 2012 Cancer Research 72:4372). This catabolic wasteful use of
energy is maladaptive in the context of the reduced food intake frequently encountered in anorectic cancer
patients. In addition we demonstrated that mobilisation of lipid reserves from fat depots was due to activation
of specific lipase enzymes in fat tissue by inflammatory signals emanating from tumours (Tsoli M et al,
2014 PLOSOne).
The current Cell Metabolism paper is the culmination of a collaboration with 2 groups in Europe exploring
how, in addition to activation of thermogenesis in pre-existing BAT, the depletion of lipid depots in cachexia is
linked with a conversion of white fat to brown fat. This "browning" process expands the potential for draining
the body even further of energy reserves during cancer cachexia. Our specific contribution was to provide the
mechanistic evidence that browning of fat is due to the release of the inflammatory cytokine IL6 from the
tumour into circulation. Use of RNAi molecular silencing techniques targeting IL6 synthesis by the tumour
completely prevented cachexia as well as the browning process. This leads to 2 important conclusions - i) that
IL6 is a key driver of cachexia and ii) that malignant cells within the tumour can be the source of IL6.
Relevance to Sydney Catalyst goal of 'improving the outcomes of those affected by cancer':
Cancer cachexia has a devastating impact on the quality of life and ability to tolerate chemotherapy for many
cancer patients, with up to 25% of cancer deaths attributed to cachexia. While muscle wasting has been the
focus of most research into cachexia, it is increasingly appreciated that fat loss and general metabolic
imbalance linked with systemic inflammation are important components of cancer cachexia. Therefore a
better understanding of the links between inflammatory mediators and the pathophysiological processes in
tissues undergoing catabolic wasting is required to alleviate the symptoms of cachexia. Our demonstration
that tumour-derived IL6 not only drives muscle wasting, but also the depletion of fat reserves and excessive
energy expenditure of fevers and nights sweats experienced by advanced cancer patients may guide therapies
to block IL6 in frail highly dependent cachectic patients. Maintenance of body mass would improve the quality
of life for many patients as well as avoid the premature termination of treatment due to involuntary weight
loss.