[en] With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Liu, Mingyang ✱; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Ren, Yu ✱; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Zhou, Zhijun ✱; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Yang, Jingxuan ✱; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Shi, Xiuhui ✱; Université de Liège - ULiège > Département de pharmacie ; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Cai, Yang ✱; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Arreola, Alex X; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA, Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Luo, Wenyi; Department of Pathology, Yale School of Medicine, New Haven, CT 06519, USA
Fung, Kar-Ming; Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Xu, Chao; Department of Biostatistics and Epidemiology, Hudson College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Nipp, Ryan D; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Bronze, Michael S; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Zheng, Lei; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Li, Yi-Ping; Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Houchen, Courtney W; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Zhang, Yuqing ✱; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: Yuqing-Zhang@ouhsc.edu
Li, Min ✱; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: Min-Li@ouhsc.edu
William and Ella Owens Medical Research Foundation VCU - Virginia Commonwealth University NIH - National Institutes of Health
Funding text :
This work was supported in part by the National Institutes of Health National Cancer Institute grants R01 CA186338, R01 CA203108, R01 CA247234, and award P30 CA225520, and by the William and Ella Owens Medical Research Foundation (M. Li). The PDX cell lines derived from pancreatic cancer patients with cachexia were established by Dr. Jose Trevino from Virginia Commonwealth University. Study conception and design: M.Liu, Y.R. Z.Z. J.Y. X.S. Y.Z. and M.Li. Data curation: M.Liu, Y.R. Z.Z. J.Y. Y.C. and X.S. Formal analysis: M.Liu, Y.R. Z.Z. J.Y. X.S. Y.C. C.X. K.F. A.A. and W.L. Visualization: M.Liu, Y.R. Z.Z. and J.Y. Resources: M.B. Y.Z. L.Z. C.H. Y.L. and M.Li. Funding acquisition: M.Li. Writing \u2013 original drafts: M.Liu, Y.R. and Z.Z. Writing \u2013 review and editing: M.Liu, Y.R. Z.Z. J.Y. X.S. R.N. A.A. M.B. Y.L. L.Z. C.H. Y.Z. and M.Li. Supervision: Y.Z. and M.Li. C.W. Houchen has ownership interest in COARE Holdings Inc.This work was supported in part by the National Institutes of Health National Cancer Institute grants R01 CA186338 , R01 CA203108 , R01 CA247234 , and award P30 CA225520 , and by the William and Ella Owens Medical Research Foundation (M. Li). The PDX cell lines derived from pancreatic cancer patients with cachexia were established by Dr. Jose Trevino from Virginia Commonwealth University.
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