Cell Reports (Nov 2024)
Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia
- Benjamin R. Pryce,
- Alexander Oles,
- Erin E. Talbert,
- Martin J. Romeo,
- Silvia Vaena,
- Sudarshana Sharma,
- Victoria Spadafora,
- Lauren Tolliver,
- David A. Mahvi,
- Katherine A. Morgan,
- William P. Lancaster,
- Eryn Beal,
- Natlie Koren,
- Bailey Watts,
- Morgan Overstreet,
- Stefano Berto,
- Suganya Subramanian,
- Kubra Calisir,
- Anna Crawford,
- Brian Neelon,
- Michael C. Ostrowski,
- Teresa A. Zimmers,
- James G. Tidball,
- David J. Wang,
- Denis C. Guttridge
Affiliations
- Benjamin R. Pryce
- Department of Pediatrics, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
- Alexander Oles
- Department of Pediatrics, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
- Erin E. Talbert
- Department of Pediatrics, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Health and Human Physiology, and the Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
- Martin J. Romeo
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
- Silvia Vaena
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
- Sudarshana Sharma
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
- Victoria Spadafora
- Department of Pediatrics, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
- Lauren Tolliver
- Department of Pediatrics, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
- David A. Mahvi
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
- Katherine A. Morgan
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
- William P. Lancaster
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
- Eryn Beal
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
- Natlie Koren
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
- Bailey Watts
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
- Morgan Overstreet
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
- Stefano Berto
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA
- Suganya Subramanian
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA
- Kubra Calisir
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
- Anna Crawford
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
- Brian Neelon
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
- Michael C. Ostrowski
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
- Teresa A. Zimmers
- Department of Cell, Developmental, and Cancer Biology, Knight Cancer Institute, Portland, Oregon Health Science University, Portland, OR 97239, USA
- James G. Tidball
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- David J. Wang
- Department of Pediatrics, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
- Denis C. Guttridge
- Department of Pediatrics, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 11
p. 114925
Abstract
Summary: Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. Nuclear factor κB (NF-κB) activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion equally derived from infiltrating monocytes and resident cells. Moreover, NF-κB-activated cells and macrophages undergo crosstalk; NF-κB+ cells recruit macrophages to inhibit regeneration and promote atrophy but, interestingly, also protect myofibers, while macrophages stimulate NF-κB+ cells to sustain an inflammatory feedforward loop. Together, we propose that NF-κB functions in multiple cells in the muscle microenvironment to stimulate macrophages that both promote and protect against muscle wasting in cancer.
