GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease

Wang, Dongdong; Day, Emily; Townsend, Logan K.; Djordjevic, Djordje; Jørgensen, Sebastian Beck; Steinberg, Gregory R.

doi:10.1038/s41574-021-00529-7

Cited by 261 publications

(203 citation statements)

References 152 publications

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“…It has been reported that the multifunctional GDF15 regulates in a series of cellular biological processes, such as food intake, energy expenditure and body weight in response to metabolic-and toxicity-induced stress (Wang et al, 2021). In this study, "HomoloGene" and phylogenetic tree analysis data con rmed the conservation of the GDF15 protein structure across different species, suggesting that similar mechanisms might exist for the normal physiological role of GDF15.…”

Section: Discussionsupporting

confidence: 59%

“…Under normal physiological conditions, circulating levels of GDF15 are in the range of 0.1-1.2 ng/ml; however, levels of GDF15 are markedly elevated in humans during cellular stress, such as in cardiac and renal failure (Ho et al, 2013;Stiermaier et al, 2014), chronic liver disease (Koo et al, 2018), various cancer (Welsh et al, 2003), chronic in ammatory diseases (Brown et al, 2007) and mitochondrial diseases (Tsai et al, 2018;Wang et al, 2021). Moreover, upregulation of GDF15 causes a dramatic reduction in food intake and weight loss (Wischhusen et al, 2020;Wang et al, 2021). These observations have led to the supposition that GDF15 does not have a normal, physiological role but is, instead, secreted as an adaptive response to disease.…”

Section: Introductionmentioning

confidence: 99%

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Pan-cancer characterization of GDF15 as a potential prognosis and immunological biomarker

Huai

Zhu

et al. 2021

Preprint

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Background Growth/differentiation factor 15 (GDF15) is a member of the TGF-b superfamily whose expression is increased in response to cellular stress and disease. Although emerging cell-or animal-based evidence supports the relationship between GDF15 and cancers, systematic pan-cancer analysis of GDF15 remains unavailable. Thus, we aimed to explore the prognostic and immunological roles of GDF15 across different types of tumors. Methods A comprehensive analysis of GDF15 in 33 types of cancer was performed based on the TCGA database. This involved an analysis of mRNA expression profiles, genetic alterations, methylation, prognostic values, immune infiltration analysis, potential biological pathways. Moreover, both the gain and loss of function strategies were used to assess the function of GDF15 in cell lines of hepatocellular carcinoma (HCC). Results GDF15 is highly expressed in most types of cancers, and there is a significant correlation between the expression of GDF15 and the prognosis of cancer patients. We have observed that GDF15 promotes the proliferation and invasion of HCC cell lines. Subsequently, methylation analyses suggested that high GDF15 expression likely resulted from hypomethylation, and immune infiltration analysis showed that GDF15 may have an impact on the changes in the tumor microenvironment. Moreover, enrichment analysis revealed that TGF-beta signaling and metabolism pathways were involved in the functional mechanisms of GDF15. Conclusions Our unpresented pan-cancer analysis of GDF15 offers a relatively comprehensive overview of the oncogenic roles of GDF15 in multiple human cancers. GDF15 may prompt HCC cellular proliferation, invasion and metastasis. All of these provides solid basement and will promote more advanced understanding the role of GDF15 in tumorigenesis and development from the perspective of clinical tumor samples and cells.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Pan-cancer characterization of GDF15 as a potential prognosis and immunological biomarker

Huai

Zhu

et al. 2021

Preprint

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“…On the other hand, the GDF15-GFRAL pathway does not seem to be implicated in appetite control in normo-physiological situations. Neither GDF15 nor GFRAL ablated mice show major alterations in body weight or food intake and preference (reviewed in [ 2 ]). Concerning its role in pathophysiology, GDF15 has been linked to cancer cachexia and side-effects of chemotherapy.…”

Section: Gdf15 As a Myokine—signaling And Physiological Significancementioning

confidence: 99%

“…More specifically, its role in appetite regulation has been emphasized since the discovery of the glial cell line-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as its hindbrain located receptor, which mediates the anorectic effects of GDF15. The general biology of GDF15 and its role in health and disease has been addressed in excellent and thorough recent reviews [ 1 , 2 ]. Here, we will focus on the role of GDF15 as a mitokine, which is induced by mitochondrial stress and dysfunction as a possible mitohormesis mediator [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of GDF15 as a Myomitokine

Johann

Kleinert

Schimrigk

2021

Cells

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Growth differentiation factor 15 (GDF15) is a cytokine best known for affecting systemic energy metabolism through its anorectic action. GDF15 expression and secretion from various organs and tissues is induced in different physiological and pathophysiological states, often linked to mitochondrial stress, leading to highly variable circulating GDF15 levels. In skeletal muscle and the heart, the basal expression of GDF15 is very low compared to other organs, but GDF15 expression and secretion can be induced in various stress conditions, such as intense exercise and acute myocardial infarction, respectively. GDF15 is thus considered as a myokine and cardiokine. GFRAL, the exclusive receptor for GDF15, is expressed in hindbrain neurons and activation of the GDF15–GFRAL pathway is linked to an increased sympathetic outflow and possibly an activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. There is also evidence for peripheral, direct effects of GDF15 on adipose tissue lipolysis and possible autocrine cardiac effects. Metabolic and behavioral outcomes of GDF15 signaling can be beneficial or detrimental, likely depending on the magnitude and duration of the GDF15 signal. This is especially apparent for GDF15 production in muscle, which can be induced both by exercise and by muscle disease states such as sarcopenia and mitochondrial myopathy.

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“…Elevated solid stress within tumors triggers the expression of Growth Differentiation Factor 15 (GDF15). GDF15 is a TGF-β-family ligand whose cellular expression also takes cues from other prevailing cellular stresses such as hypoxia and nutritional stress ( Patel et al, 2019 ) ( Wang et al, 2021 ). GDF15 activates the Akt-signaling pathway in the cancer cells leading to invasiveness, and migration ( Kalli et al, 2019 ) ( Nia et al, 2020 ).…”

Section: Mechanical Traitsmentioning

confidence: 99%

Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits

Maneshi

Mason

Dongre

et al. 2021

Front. Cell Dev. Biol.

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Pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes among cancers with a 5-years survival rate of below 10%. This is a result of late diagnosis and the lack of effective treatments. The tumor is characterized by a highly fibrotic stroma containing distinct cellular components, embedded within an extracellular matrix (ECM). This ECM-abundant tumor microenvironment (TME) in PDAC plays a pivotal role in tumor progression and resistance to treatment. Cancer-associated fibroblasts (CAFs), being a dominant cell type of the stroma, are in fact functionally heterogeneous populations of cells within the TME. Certain subtypes of CAFs are the main producer of the ECM components of the stroma, with the most abundant one being the collagen family of proteins. Collagens are large macromolecules that upon deposition into the ECM form supramolecular fibrillar structures which provide a mechanical framework to the TME. They not only bring structure to the tissue by being the main structural proteins but also contain binding domains that interact with surface receptors on the cancer cells. These interactions can induce various responses in the cancer cells and activate signaling pathways leading to epithelial-to-mesenchymal transition (EMT) and ultimately metastasis. In addition, collagens are one of the main contributors to building up mechanical forces in the tumor. These forces influence the signaling pathways that are involved in cell motility and tumor progression and affect tumor microstructure and tissue stiffness by exerting solid stress and interstitial fluid pressure on the cells. Taken together, the TME is subjected to various types of mechanical forces and interactions that affect tumor progression, metastasis, and drug response. In this review article, we aim to summarize and contextualize the recent knowledge of components of the PDAC stroma, especially the role of different collagens and mechanical traits on tumor progression. We furthermore discuss different experimental models available for studying tumor-stromal interactions and finally discuss potential therapeutic targets within the stroma.

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GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease

Cited by 261 publications

References 152 publications

Pan-cancer characterization of GDF15 as a potential prognosis and immunological biomarker

Pan-cancer characterization of GDF15 as a potential prognosis and immunological biomarker

The Role of GDF15 as a Myomitokine

Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits

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