Journal article

Tumor-derived MMPs regulate cachexia in a Drosophila cancer model

William Lodge, Michael Zavortink, Sofia Golenkina, Francesca Froldi, Callum Dark, Shane Cheung, Benjamin L Parker, Ronnie Blazev, Daniel Bakopoulos, Elizabeth L Christie, Verena C Wimmer, Brigette C Duckworth, Helena E Richardson, Louise Y Cheng

DEVELOPMENTAL CELL | CELL PRESS | Published : 2021

Abstract

Cachexia, the wasting syndrome commonly observed in advanced cancer patients, accounts for up to one-third of cancer-related mortalities. We have established a Drosophila larval model of organ wasting whereby epithelial overgrowth in eye-antennal discs leads to wasting of the adipose tissue and muscles. The wasting is associated with fat-body remodeling and muscle detachment and is dependent on tumor-secreted matrix metalloproteinase 1 (Mmp1). Mmp1 can both modulate TGFβ signaling in the fat body and disrupt basement membrane (BM)/extracellular matrix (ECM) protein localization in both the fat body and the muscle. Inhibition of TGFβ signaling or Mmps in the fat body/muscle using a QF2-QUAS b..

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Grants

Awarded by ARC Future fellowship


Funding Acknowledgements

We are grateful to Douglas Allen, Ken Brodie, Andrea Page-McCaw, Donna Denton, Philip Batterham, Donal O'Shea, Maria Del Carmen Diaz de la Loza, Barry Thompson, and Konrad Basler for generous sharing of reagents. We would like to thank Bloomington Drosophila Stock Center, Vienna Drosophila Resource Center, Fly Stocks of National Institute of Genetics, Kyoto Stock Center, Developmental Studies Hybridoma Bank and Addgene for fly stocks and plasmids. We would like to thank Kelly Rogers and Centre for Dynamic Imaging at the Walter and Eliza Hall Institute of Medical Research for help with Light sheet imaging. We would like to also thank OZDros for Drosophila quarantine, Peter MacCallum Cancer Institute Microscopy core and Biological Optical Microscopy platform at the University of Melbourne for technical assistance. We are grateful to Kellie Veen, Edel Alvarez, and Qian Dong for critical reading of the manuscript. We also thank Zoe Uberoi and Kellie Veen for graphical assistance. L.Y.C. is funded by an ARC Future fellowship FT80100255, L.Y.C.'s laboratory is supported by funding from the NHMRC, ARC and the Peter MacCallum Cancer Foundation.