A TGF-β/KLF10 signaling axis regulates atrophy-associated genes to induce muscle wasting in pancreatic cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 34; p. e2215095120
• Main Authors: Dasgupta, Aneesha, Gibbard, Daniel F, Schmitt, Rebecca E, Arneson-Wissink, Paige C, Ducharme, Alexandra M, Bruinsma, Elizabeth S, Hawse, John R, Jatoi, Aminah, Doles, Jason D
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.08.2023
• Subjects: Animal models; Animals; Appetite; Atrophy; Autophagy; Binding; Bioinformatics; Biological Sciences; Cachexia; Cachexia - genetics; Calcium signalling; Colon cancer; Complications; Dietary supplements; Early Growth Response Transcription Factors - genetics; Early Growth Response Transcription Factors - metabolism; Growth factors; Humans; In vivo methods and tests; Krueppel-like factor; Kruppel-Like Transcription Factors - metabolism; Lung cancer; Metabolism; Mice; Muscle, Skeletal - metabolism; Muscles; Muscular Atrophy - genetics; Pancreatic cancer; Pancreatic Neoplasms - complications; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Skeletal muscle; Stimulants; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Ubiquitin; KLF10; TGF-β; pancreatic cancer; muscle wasting; cachexia
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2215095120

Cancer cachexia, and its associated complications, represent a large and currently untreatable roadblock to effective cancer management. Many potential therapies have been proposed and tested-including appetite stimulants, targeted cytokine blockers, and nutritional supplementation-yet highly effective therapies are lacking. Innovative approaches to treating cancer cachexia are needed. Members of the Kruppel-like factor (KLF) family play wide-ranging and important roles in the development, maintenance, and metabolism of skeletal muscle. Within the KLF family, we identified KLF10 upregulation in a multitude of wasting contexts-including in pancreatic, lung, and colon cancer mouse models as well as in human patients. We subsequently interrogated loss-of-function of KLF10 as a potential strategy to mitigate cancer associated muscle wasting. In vivo studies leveraging orthotopic implantation of pancreas cancer cells into wild-type and KLF10 KO mice revealed significant preservation of lean mass and robust suppression of pro-atrophy muscle-specific ubiquitin ligases Trim63 and Fbxo32, as well as other factors implicated in atrophy, calcium signaling, and autophagy. Bioinformatics analyses identified Transforming growth factor beta (TGF-β), a known inducer of KLF10 and cachexia promoting factor, as a key upstream regulator of KLF10. We provide direct in vivo evidence that KLF10 KO mice are resistant to the atrophic effects of TGF-β. ChIP-based binding studies demonstrated direct binding to , a known wasting-associated atrogene. Taken together, we report a critical role for the TGF-β/KLF10 axis in the etiology of pancreatic cancer-associated muscle wasting and highlight the utility of targeting KLF10 as a strategy to prevent muscle wasting and limit cancer-associated cachexia.