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Publications

Journal Article Ahead of print 1 citation

PubMed: 42678278 DOI: 10.1158/2159-8290.CD-26-0045

Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia.

Cancer Discov

Authors: Juliano Machado, Vignesh Karthikaisamy, Hermine Mohr, Doris Kaltenecker, Pia Benedikt, Pauline Morigny, Amit Mhamane, Julia Geppert, Amy Rose Fumo, Kerstin Haase, Estefania Simoes, Joanna D C C Lima, Anastasia Georgiadi, Achim Krüger, José Pinhata Otoch, Marc E Martignoni, Vickie E Baracos, Mariam Jamal-Hanjani, Marilia C L Seelaender, Olga Prokopchuk, Julia Szendrödi, Maria Rohm, Stephan Herzig, Mauricio Berriel Diaz

Affiliations

  • Institute for Diabetes and Cancer (IDC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany.
  • Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany.
  • German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • International Helmholtz Research School for Diabetes, Helmholtz Munich, Neuherberg, Germany.
  • Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, United Kingdom.
  • Cancer Metastasis Lab, University College London Cancer Institute, London, United Kingdom.
  • Department of Oncology, University College London Hospitals, London, United Kingdom.
  • Cancer Metabolism Research Group, LIM 26 HCFMUSP and Department of Surgery, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil.
  • Institute of Experimental Oncology and Therapy Research, Technical University of Munich, School of Medicine, Munich, Germany.
  • University Hospital, University of São Paulo, São Paulo, Brazil.
  • Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
  • Division of Palliative Care Medicine, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada.
  • Chair Molecular Metabolic Control, Technical University of Munich, Munich, Germany.

Abstract

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.

MeSH

Muscular Atrophy, Cells, Muscle Cells, Muscles, Atrophy, Fibrosis, Neoplasms, Therapeutics, Cachexia, Cancer-Associated Cachexia