Drosophila as a model system to study local and systemic mechanisms of cancer cachexia

Supervisors: Julia Cordero (University of Glasgow), Jennifer Morton (CRUK Beatson Institute)

Cancer cachexia is a paraneoplastic syndrome defined as the "loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment" [1]. Cachexia is a multifactorial and multi-organ pathology of complex and largely unknown aetiology, which can cause up to 30% of late-stage cancer-related deaths, including in pancreatic cancer [2]. How individual factors and tissues contribute to the overall pathology, including the tumour outcome, is largely unclear. Consequently, there is not a defined standard of care for cancer cachexia.

Pancreatic cancer shows the highest rate of associated cachexia [3]. Over 85% of pancreatic cancer patients develop cachexia [4]. There is an urgent unmet clinical need to identify the mechanisms behind the development of cachexia-associated tissue wasting, and its systemic and tumour-intrinsic impact [5]. The major goal of the PRECISION-Panc network at our institution is to learn more about pancreatic cancer and ultimately identify the molecular profile of individual patients so that we can design the right trial for the right patient. Understanding the mechanisms of cancer cachexia is crucial towards such a goal. While multiple studies, predominantly in mouse models, have focused on how tumours my lead to peripheric tissue wasting, much less is understood on the impact of peripheric tissue wasting to the tumorigenesis process and overall systemic status of the host.

We have recently generated a genetically defined Drosophila model, which recapitulates key aspects of human cancer cachexia, including severe wasting of skeletal muscle and systemic inflammation. In this proposal we aim to:

1- Fully characterize a novel Drosophila model of cancer cachexia.

2- Identify molecular mechanisms driving muscle wasting in our Drosophila model of cancer cachexia and their systemic and tumour-intrinsic impact.

3- Translate key findings from Drosophila into a cachectic mouse model of pancreatic cancer.

Altogether, our approach will allow elucidation of conserved mechanisms of cancer cachexia and its functional relevance to the tumorigenesis process and overall host wellbeing.

1. Fearon, K., et al., Definition and classification of cancer cachexia: an international consensus. Lancet Oncol, 2011. 12(5): p. 489-95.
2. Argiles, J.M., et al., Cancer cachexia: understanding the molecular basis. Nat Rev Cancer, 2014. 14(11): p. 754-62.
3. Wallengren, O., K. Lundholm, and I. Bosaeus, Diagnostic criteria of cancer cachexia: relation to quality of life, exercise capacity and survival in unselected palliative care patients. Support Care Cancer, 2013. 21(6): p. 1569-77.
4. Bachmann, J., et al., Pancreatic cancer related cachexia: influence on metabolism and correlation to weight loss and pulmonary function. BMC Cancer, 2009. 9: p. 255.
5. Lok, C., Cachexia: The last illness. Nature, 2015. 528(7581): p. 182-3.

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