Tumor-borne ADAMTSL4 drives cancer cachexia via TGFβ signaling pathway

Cancer cachexia (CCx) is a multifactorial wasting disorder in patients with cancer characterized by involuntary body weight loss. Whereas CCx is associated with reduced quality of life and poor survival, no approved pharmacological intervention exists. Here we show that elevated circulating levels of the tumour-derived glycoprotein ADAMTSL4 were associated with weight loss in various preclinical CCx models as well as in cachectic patients with different cancers. ADAMTSL4 overexpression in non-cachexia-inducing tumour cells conferred cachexia-inducing properties upon exposure of cultured myocytes and adipocytes as well as implantation in mice. Reversely, genetic ADAMTSL4 deletion in cachexia-inducing cancer cells markedly repressed wasting phenotypes both in vitro and in vivo. Ligand-receptor capture technology identified the latency-associated peptide of TGF-β1 as ADAMTSL4 target on muscle cell surface. ADAMTSL4 mediated muscle atrophy and adipose tissue wasting through local TGF-β1 activation, sensitive to inhibition of TGFβR1 or knockdown of proTGF-β1. Given the conserved correlation between circulating ADAMTSL4 and skeletal muscle TGF pathway component expression in an independent human cancer patient cohort, our data suggest that blockade of ADAMTSL4 function represents a first rational approach towards efficient cancer cachexia pharmacotherapy.