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

doi:10.1016/j.devcel.2021.08.008

Tumor-derived MMPs regulate cachexia in a Drosophila cancer model

Dev Cell. 2021 Sep 27;56(18):2664-2680.e6. doi: 10.1016/j.devcel.2021.08.008. Epub 2021 Sep 1.

Affiliations

¹ Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
² Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC 3000, Australia.
³ Department of Anatomy and Physiology, the University of Melbourne, Melbourne, VIC 3000, Australia.
⁴ Centre for Dynamic Imaging, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁵ Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
⁶ Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
⁷ Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC 3000, Australia; Department of Anatomy and Physiology, the University of Melbourne, Melbourne, VIC 3000, Australia. Electronic address: louise.cheng@petermac.org.

PMID: 34473940
DOI: 10.1016/j.devcel.2021.08.008

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 binary expression system rescues muscle wasting in the presence of tumor. Altogether, our study proposes that tumor-derived Mmps are central mediators of organ wasting in cancer cachexia.

Keywords: Drosophila; MMP; TGFβ signaling; Timp; cachexia; fat body; interorgan crosstalk; muscle.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / metabolism*
Animals
Basement Membrane / metabolism
Drosophila / metabolism
Extracellular Matrix / metabolism
Matrix Metalloproteinases / metabolism*
Muscle, Skeletal / metabolism*
Muscular Atrophy / metabolism
Neoplasms / metabolism*

Substances

Matrix Metalloproteinases