MAP3K11/GDF15 axis is a critical driver of cancer cachexia

Abstract

BackgroundCancer 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.MethodsGenetically 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.ResultsUtilizing 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.ConclusionsThe 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.

Association of Growth Differentiation Factor 15 with Mortality in a Prospective Hemodialysis Cohort

“…With respect to protein-energy wasting pathways, GDF15 acts directly upon the hypothalamus to reduce food intake and energy expenditure [20]. In animal models, GDF15 administration has been shown to lead to satiety and weight reduction, which has been reversed or prevented by the administration of anti-GDF15 neutralizing antibodies [20,26,42]. Notably, in the sensitivity analyses we found that the relationship between higher GDF15 levels and higher mortality risk persisted following adjustment for body size (i.e., BMI) and protein intake (i.e., nPCR), suggesting that cardiovascular pathways may be implicated.…”

“…Indeed, in cancer-associated cachexia, circulating GDF15 levels correlate with weight loss, lower lean body and fat mass, weaker handgrip strength, and worse survival [21]. These findings bear particular relevance to the hemodialysis population, in whom weight loss and protein-energy wasting are among the most potent predictors of mortality, including cardiovascular death [22,23,24,25,26]. …”

STAT3 in the systemic inflammation of cancer cachexia

“…Circulating mediators of inflammation implicated in cancer-induced muscle wasting include members of the TNF, IL-6, IFN, and IL-2 families of cytokines, although the only factors thus far consistently correlated with cachexia overall are IL-6, Activin A and Growth Differentiation Factor (GDF)-15, the latter two members of the Transforming Growth Factor-β superfamily [118–121]. The relationship is a general one, however, with the concentrations of these factors highly heterogeneous across patients.…”

“…Careful and numerous genetic studies demonstrate that endogenous STAT3 plays essential, protective roles for cardiac size and function [118]. Male mice with cardiomyocte-specific deletion of STAT3 develop heart failure, while female mice develop post-partum cardiac myopathy.…”

Management of severe pregnancy sickness and hyperemesis gravidarum

“…GDF15 is a hormone known to affect appetite, and is highly expressed in placental trophoblasts and decidual stromal cells. High GDF15 is a key driver in cancer cachexia,12 which is characterised by symptoms similar to HG: nausea, weight loss, and muscle wasting. Further research replicating these findings and establishing causality is needed.…”