Convergent insulin and TGF‐β signalling drives cancer cachexia by promoting aberrant fat body ECM accumulation in a Drosophila tumour model

In this study, we found that in the adipose tissue of wildtype animals, insulin and TGF‐β signalling converge via a BMP antagonist short gastrulation (sog) to regulate ECM remodelling. In tumour bearing animals, Sog also modulates TGF‐β signalling to regulate ECM accumulation in the fat body. TGF‐β signalling causes ECM retention in the fat body and subsequently depletes muscles of fat body‐derived ECM proteins. Activation of insulin signalling, inhibition of TGF‐β signalling, or modulation of ECM levels via SPARC, Rab10 or Collagen IV in the fat body, is 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. Synopsis During cancer cachexia, insulin and TGF‐β signalling converge in the fat body via Sog to hinder ECM secretion, which in turn affects muscle integrity. Eye tumour models employing RasV12 together with Scrib RNAi or Dlg RNAi were used to study how inter‐organ communication affects fat body and muscle integrity in cancer cachexia. TGF‐β and insulin signalling converge in the fat body to control ECM secretion via Sog. Modulating ECM secretion from the fat body rescues muscle integrity in the presence of tumour. During cancer cachexia, insulin and TGF‐β signalling converge in the fat body via Sog to hinder ECM secretion, which in turn affects muscle integrity.