Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival

Amelia J Johnston; Kate T Murphy; Laura Jenkinson; David Laine; Kerstin Emmrich; Pierre Faou; Ross Weston; Krishnath M Jayatilleke; Jessie Schloegel; Gert Talbo; Joanne L Casey; Vita Levina; W Wei-Lynn Wong; Helen Dillon; Tushar Sahay; Joan Hoogenraad; Holly Anderton; Cathrine Hall; Pascal Schneider; Maria Tanzer; Michael Foley; Andrew M Scott; Paul Gregorevic; Spring Yingchun Liu; Linda C Burkly; Gordon S Lynch; John Silke; Nicholas J Hoogenraad

doi:10.1016/j.cell.2015.08.031

Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival

Cell. 2015 Sep 10;162(6):1365-78. doi: 10.1016/j.cell.2015.08.031.

Authors

Amelia J Johnston¹, Kate T Murphy², Laura Jenkinson³, David Laine³, Kerstin Emmrich³, Pierre Faou³, Ross Weston³, Krishnath M Jayatilleke³, Jessie Schloegel³, Gert Talbo³, Joanne L Casey³, Vita Levina³, W Wei-Lynn Wong⁴, Helen Dillon³, Tushar Sahay³, Joan Hoogenraad³, Holly Anderton⁵, Cathrine Hall⁶, Pascal Schneider⁷, Maria Tanzer⁶, Michael Foley³, Andrew M Scott⁸, Paul Gregorevic⁹, Spring Yingchun Liu¹⁰, Linda C Burkly¹¹, Gordon S Lynch², John Silke⁵, Nicholas J Hoogenraad¹²

Affiliations

¹ Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia. Electronic address: a.johnston@latrobe.edu.au.
² Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Melbourne, VIC 3010, Australia.
³ Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
⁴ Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
⁵ Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; The Walter and Eliza Hall Institute, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3050, Australia.
⁶ The Walter and Eliza Hall Institute, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3050, Australia.
⁷ Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland.
⁸ Olivia Newton-John Cancer Research Institute, Melbourne, VIC 3084, Australia; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
⁹ Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
¹⁰ Broad Institute, MIT and Harvard, Cambridge, MA 02142, USA.
¹¹ Department of Immunology, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
¹² Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia. Electronic address: n.hoogenraad@latrobe.edu.au.

PMID: 26359988
DOI: 10.1016/j.cell.2015.08.031

Abstract

The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Antibodies, Monoclonal / administration & dosage
Atrophy / drug therapy
Cachexia / drug therapy*
Cachexia / pathology
Cell Death
Colonic Neoplasms / drug therapy
Cytokine TWEAK
Female
Humans
Lung Neoplasms / drug therapy
Mice
Mice, Inbred BALB C
Molecular Sequence Data
Muscle Development
Neoplasms / metabolism
Neoplasms / pathology*
Receptors, Tumor Necrosis Factor / antagonists & inhibitors*
Receptors, Tumor Necrosis Factor / chemistry
Receptors, Tumor Necrosis Factor / metabolism
Sequence Alignment
Signal Transduction
TWEAK Receptor
Tumor Necrosis Factors / metabolism

Substances

Antibodies, Monoclonal
Cytokine TWEAK
Receptors, Tumor Necrosis Factor
TNFRSF12A protein, human
TWEAK Receptor
Tnfrsf12a protein, mouse
Tnfsf12 protein, mouse
Tumor Necrosis Factors