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Machado, J. ; Karthikaisamy, V. ; Mohr, H. ; Kaltenecker, D. ; Benedikt-Kühnast, P. ; Morigny, P. ; Mhamane, A. ; Geppert, J. ; Fumo, A.R. ; Haase, K.* ; Simoes Fernandez, E. ; Lima, J.D.C.C.* ; Georgiadi, A. ; Krüger, A.* ; Otoch, J.P.* ; Martignoni, M.E.* ; Baracos, V.E.* ; Jamal-Hanjani, M.* ; Seelaender, M.C.L.* ; Prokopchuk, O.* ; Szendrödi, J.* ; Rohm, M. ; Herzig, S. ; Berriel Diaz, M.

Tumor-secreted ADAMTSL4 activates latent TGF-β1 to drive cancer cachexia.

Cancer Discov., DOI: 10.1158/2159-8290.CD-26-0045 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
UNLABELLED: Cancer cachexia is a devastating wasting syndrome with no approved therapies. In this study, we identify the tumor-derived glycoprotein ADAMTSL4 as a circulating factor associated with body weight loss in preclinical cachexia models and patients with colorectal and lung cancers. In mice, Adamtsl4 overexpression converted non-cachexia-inducing tumors into cachexia-inducing tumors, whereas its deletion in cachexia-inducing tumors spared fat and muscle, blunted muscle atrophy signatures, and reduced cachexia severity. ADAMTSL4 engages the latency-associated peptide (LAP) of TGFβ1, promoting local activation of TGFβ1 at muscle cell membranes. Genetic blockade of proTGFβ1 or pharmacologic inhibition of TGFβ signaling reduced ADAMTSL4-dependent wasting in adipocytes and muscle cells. Suppression of tumor-derived ADAMTSL4 attenuated skeletal muscle fibrosis in mice. Together, the association between increased circulating ADAMTSL4 levels and TGFβ-driven muscle atrophy and fibrosis gene signatures in patients with cachectic cancer identifies ADAMTSL4 as an upstream regulator of TGFβ1 and a potential therapeutic target in cancer cachexia. SIGNIFICANCE: Cancer cachexia lacks effective therapies and remains a major cause of cancer-related morbidity and mortality. We identify tumor-derived ADAMTSL4 as an upstream regulator of latent TGFβ activation via LAP engagement that promotes multiorgan wasting and fibrosis-related remodeling. Targeting ADAMTSL4 may provide a selective therapeutic strategy without systemic TGFβ pathway blockade.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 2159-8274
e-ISSN 2159-8290
Journal Cancer Discovery
Publisher American Association for Cancer Research (AACR)
Publishing Place Philadelphia, Pa.
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
Grants Helmholtz Association - Initiative and Networking Fund
Helmholtz Research School for Diabetes
Edith-Haberland-Wagner Foundation