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Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer

Author

Listed:
  • Andre Lima Queiroz

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Ezequiel Dantas

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Shakti Ramsamooj

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Anirudh Murthy

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Mujmmail Ahmed

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Elizabeth R. M. Zunica

    (Pennington Biomedical Research Center)

  • Roger J. Liang

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Jessica Murphy

    (Weill Cornell Medicine
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Corey D. Holman

    (Weill Cornell Medicine)

  • Curtis J. Bare

    (Weill Cornell Medicine)

  • Gregory Ghahramani

    (Weill Cornell Medicine)

  • Zhidan Wu

    (Pfizer Global R&D)

  • David E. Cohen

    (Weill Cornell Medicine)

  • John P. Kirwan

    (Pennington Biomedical Research Center)

  • Lewis C. Cantley

    (Weill Cornell Medicine)

  • Christopher L. Axelrod

    (Pennington Biomedical Research Center)

  • Marcus D. Goncalves

    (Weill Cornell Medicine
    Weill Cornell Medicine)

Abstract

Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.

Suggested Citation

  • Andre Lima Queiroz & Ezequiel Dantas & Shakti Ramsamooj & Anirudh Murthy & Mujmmail Ahmed & Elizabeth R. M. Zunica & Roger J. Liang & Jessica Murphy & Corey D. Holman & Curtis J. Bare & Gregory Ghahra, 2022. "Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32135-0
    DOI: 10.1038/s41467-022-32135-0
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    1. Hongbin Ji & Matthew R. Ramsey & D. Neil Hayes & Cheng Fan & Kate McNamara & Piotr Kozlowski & Chad Torrice & Michael C. Wu & Takeshi Shimamura & Samanthi A. Perera & Mei-Chih Liang & Dongpo Cai & Geo, 2007. "LKB1 modulates lung cancer differentiation and metastasis," Nature, Nature, vol. 448(7155), pages 807-810, August.
    2. Serkan Kir & James P. White & Sandra Kleiner & Lawrence Kazak & Paul Cohen & Vickie E. Baracos & Bruce M. Spiegelman, 2014. "Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia," Nature, Nature, vol. 513(7516), pages 100-104, September.
    3. Jan Bert Van Klinken & Sjoerd A A van den Berg & Louis M Havekes & Ko Willems Van Dijk, 2012. "Estimation of Activity Related Energy Expenditure and Resting Metabolic Rate in Freely Moving Mice from Indirect Calorimetry Data," PLOS ONE, Public Library of Science, vol. 7(5), pages 1-12, May.
    4. Man Zhang & Wei Yang & Peng Wang & Yu Deng & Yu-Ting Dong & Fang-Fang Liu & Rui Huang & Peng Zhang & Ya-Qi Duan & Xin-Dong Liu & Dandan Lin & Qian Chu & Bo Zhong, 2020. "CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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    1. Qingtao Sun & Daniëlle Lisdonk & Miriam Ferrer & Bruno Gegenhuber & Melody Wu & Youngkyu Park & David A. Tuveson & Jessica Tollkuhn & Tobias Janowitz & Bo Li, 2024. "Area postrema neurons mediate interleukin-6 function in cancer cachexia," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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