title: MAP3K11/GDF15 axis is a critical driver of cancer cachexia.
abstract: Cancer associated cachexia affects the majority of cancer patients during the course of the disease and thought to be directly responsible for about a quarter of all cancer deaths. Current evidence suggests that a pro-inflammatory state may be associated with this syndrome although the molecular mechanisms responsible for the development of cachexia are poorly understood. The purpose of this work was the identification of key drivers of cancer cachexia that could provide a potential point of intervention for the treatment and/or prevention of this syndrome.
  
  
  
  Genetically engineered and xenograft tumour models were used to dissect the molecular mechanisms driving cancer cachexia. Cytokine profiling from the plasma of cachectic and non-cachectic cancer patients and mouse models was utilized to correlate circulating cytokine levels with the cachexia phenotype.
  
  
  
  Utilizing engineered tumour models we identified MAP3K11/GDF15 pathway activation as a potent inducer of cancer cachexia. Increased expression and high circulating levels of GDF15 acted as a key mediator of this process. In animal models, tumour-produced GDF15 was sufficient to trigger the cachexia phenotype. Elevated GDF15 circulating levels correlated with the onset and progression of cachexia in animal models and in patients with cancer. Inhibition of GDF15 biological activity with a specific antibody reversed body weight loss and restored muscle and fat tissue mass in several cachectic animal models regardless of their complex secreted cytokine profile.
  
  
  
  The combination of correlative observations, gain of function, and loss of function experiments validated GDF15 as a key driver of cancer cachexia and as a potential therapeutic target for the treatment and/or prevention of this syndrome.
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Lorena
authors.identifier: 0000-0002-9474-2018
authors.initials: L
authors.lastname: Lerner
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Tao
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Nicoletti
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Feng
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Krieger
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mazsa
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Zakir
authors.initials: Z
authors.lastname: Siddiquee
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Ruoji
authors.initials: R
authors.lastname: Wang
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA; Novartis Institutes for BioMedical Research 211 Massachusetts Ave. Cambridge MA 02139 USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Huang
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA; Moderna Therapeutics 200 Technology Square Cambridge MA 02139 USA.
authors.forename: Luhua
authors.initials: L
authors.lastname: Shen
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA; Stealth Peptides Inc.275 Grove Street, Ste.3-107 Newton MA 02466 USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.affiliation: McGill Nutrition and Performance Laboratory; (MNUPAL) McGill University Health Centre (MUHC) Montreal Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vigano
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA; Enumeral Biomedical Corp One Kendall Square Building 400 Cambridge MA 02139 USA.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Chiu
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Weng
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA; POTENZA Therapeutics 700 Main Street Cambridge MA 02139 USA.
authors.forename: William
authors.initials: W
authors.lastname: Winston
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Solly
authors.initials: S
authors.lastname: Weiler
authors.affiliation: AVEO Oncology One Broadway 14th Floor Cambridge MA 02142 USA.
authors.forename: Jeno
authors.initials: J
authors.lastname: Gyuris
keywords: Cancer cachexia; GDF15; MAP3K11; MIC‐1; MLK3