Convergent Insulin and TGF-β signalling drives cancer cachexia by promoting aberrant fatbody ECM accumulation in a Drosophila tumour model

Cancer cachexia is a wasting disease suffered by advanced stage cancer patients and ultimately causes ∼30% of cancer mortalities. Clinical observations have shown that extracellular matrix (ECM) remodelling which leads to fibrosis in the adipose tissue is a key feature of cancer cachexia. However, the molecular regulators of adipose ECM remodelling are not known and how this leads to muscle wasting is unclear. In this study, using a Drosophila cachexia model, we found that in the adipose tissue of both wildtype and tumour bearing animals, insulin and TGF-β signalling converge via a BMP antagonist short gastrulation ( sog ) to regulate ECM remodelling. In tumour bearing animals, the aberrant ECM accumulation in the fatbody, contributes towards muscle detachment by preventing ECM secretion and subsequently depleting muscles of fatbody-secreted ECM proteins. Strikingly, activation of insulin signalling, inhibition of TGF-β signalling, or modulation of ECM secretion via SPARC or Rab10 in the fatbody, was able to rescue tissue wasting in the presence of tumour. Together, our study highlights the importance of adipose ECM remodelling in the context of cancer cachexia.