Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia

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 Details

Journal
Cancer Discovery
Published
2026-09-01
DOI
https://doi.org/10.1158/2159-8290.cd-26-0045
Primary Topic
Muscle Physiology and Disorders
Type
article
Field-Weighted Citation Impact
0.00

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article

Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia

Amit Mhamane, Vickie E. Baracos, Marília Seelaender, Joanna D.C.C. Lima et al.
Cancer Discovery
Muscle Physiology and Disorders
article

Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia

Amit Mhamane, Vickie E. Baracos, Marília Seelaender, Joanna D.C.C. Lima, Olga Prokopchuk, Julia Geppert, Pia Benedikt, Hermine Mohr, José Pinhata Otoch, Doris Kaltenecker, Mauricio Berriel Díaz, Pauline Morigny, Mariam Jamal‐Hanjani, Vignesh Karthikaisamy, Anastasia Georgiadi, Maria Rohm, Estefanía Simoes, Stephan Herzig, Achim Krüger, Kerstin Haase, Marc E. Martignoni, Julia Szendroedi, Amy Rose Fumo, Juliano Machado
article en

Abstract

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.

Cancer Discovery
University College Hospital (GB), University College London Hospitals NHS Foundation Trust (GB), University of Alberta (CA), Heidelberg University (DE), University Hospital Heidelberg (DE), TUM Klinikum (DE), Helmholtz Zentrum München (DE), London Cancer (GB), Diabetesinstitut Heidelberg (DE), Hospital Universitário da Universidade de São Paulo (BR), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), CRUK Lung Cancer Centre of Excellence (GB), Deutsches Diabetes-Zentrum e.V. (DE), German Center for Diabetes Research (DE), Heinrich Heine University Düsseldorf (DE), University College London (GB), Technical University of Munich (DE)
Cancer Research UK, European Commission, Deutsche Forschungsgemeinschaft, Else Kröner-Fresenius-Stiftung, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 18%
Muscle Physiology and Disorders
DOIOpen Access PDFOpenAlex
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