Chemerin Tips the Scales in ccRCC to Evade Ferroptosis

Clear cell renal cell carcinomas (ccRCC) are aggressive cancers of the kidney histologically characterized by the accumulation of cytoplasmic lipid droplets. These tumors demonstrate extensive changes to all corners of the tumor metabolome, including nearly uniform depletion of amino acids, accumulation of ROS-mediating metabolites and cofactors, and the eponymous accumulation of glycogen and lipids (1). To some extent, these metabolomic changes arise as a consequence of biallelic inactivation of the VHL tumor suppressor gene, which promotes stabilization of HIF1A and HIF2A and a pseudohypoxic state. However, although some of the distinguishing metabolic phenotypes (such as suppression of mitochondrial respiration in favor of aerobic glycolysis) of ccRCC can be ascribed to the immediate consequences of HIF stabilization, the molecular drivers of most of the metabolomic alterations in ccRCC are uncharacterized. Perhaps more important, the evolutionary advantage endowed by such metabolic adaptations to the tumor remains the subject of intense scientific investigation.

Obesity is an important and paradoxical clinical factor in the management of ccRCC. As with many other cancers, ccRCC has a higher incidence among obese patients: the risk of developing RCC increases by 24% for men and 34% for women for every 5-kg/m² rise in body mass index (BMI; refs. 2, 3). Counterintuitively, obese patients with ccRCC demonstrate superior outcomes following nephrectomy and tyrosine kinase therapy. Similarly, obese patients with metastatic RCC receiving immunotherapy demonstrate better outcomes relative to their normal-weight counterparts. When taken together with the lipid-laden molecular characteristics of ccRCC, these compelling epidemiologic and clinical observations suggest that a deep connection ties the systemic physiology and health of patients with ccRCC to their clinical trajectory. The molecular mechanisms connecting obesity to RCC are poorly understood but have been proposed to involve alterations to tissue oxygen tension, metabolic dysfunction, and chronic inflammation (4, 5).

In this issue of Cancer Discovery, Tan and colleagues (6) report that a key signaling molecule secreted from adipose tissue drives the accumulation of fatty acid droplets in ccRCC cells in order to evade cell death by ferroptosis. Motivated by the observation that ccRCC tumors exhibit evidence of transdifferentiation into an adipose-like phenotype, the authors examined gene expression data for evidence of ccRCC-specific overexpression of adipokines. This analysis identified chemerin as specifically overexpressed in ccRCC tumors. Subsequent analysis confirmed that chemerin was expressed specifically in ccRCC tumor cells and not other cells in the tumor microenvironment and that its expression was associated with high-stage disease. Circulating plasma chemerin levels were elevated in patients with ccRCC relative to controls and correlated to the BMI of the patient. Together, these data suggested that chemerin is a ccRCC-relevant adipokine with both a paracrine and an autocrine mechanism of action.

Through a variety of knockdown/knockout experiments, the authors established that ccRCC tumors rely on chemerin expression to support growth in vitro and in vivo. Metabolically, chemerin inhibition produced potent transcriptomic and metabolomic phenotypes that fundamentally altered the way tumor cells metabolize lipids. At a high level, chemerin inhibition reduced overall lipid deposition in cells, increased the expression of β-oxidation genes, and fundamentally reorganized the lipid composition of cells toward a more oxidized state. Inhibition of β-oxidation rescued growth defects associated with chemerin inhibition, suggesting that chemerin-mediated lipid reprogramming is required for ccRCC growth.

The authors identified two complementary lipid-dependent mechanisms by which chemerin inhibition mediates cell death. First, through reorganization of the lipidome, chemerin inhibition increases the abundance of polyunsaturated fatty acids, which can induce ferroptosis through lipid peroxidation (7). Second, the authors noted a reduction of CoQ10 and other lipid molecules required for the function of complex IV of the mitochondrial respiratory chain. Such a reduction in complex IV abundance in the presence of chemerin inhibition resulted in a reduction of oxygen consumption and ATP production, potentially producing an imbalance in electron flow in the respiratory chain and an increase in reactive oxygen species. The authors further found that chemerin expression in ccRCC is VHL-dependent, which they linked to the VHL/HIF2α axis via the zinc finger DNA-binding transcription factor KLF6. Finally, the authors demonstrated that treatment of xenografted mice with monoclonal antibody against chemerin significantly reduced tumor growth, suggesting that targeting of chemerin may represent a new therapeutic target in ccRCC. These provocative data provide a strong rationale to investigate and establish the role of chemerin in driving aspects of the tumor metabolome and in mediating ferroptotic phenotypes in humans.

Overall, the study by Tan and colleagues (6) nominates a new metabolic paradigm underlying ccRCC pathophysiology, whereby a circulating factor acts as a paracrine and autocrine mediator between physiologic obesity and tumor metabolism itself. This model adds a new layer of complexity to the question of how obesity increases the risk of tumor development but is a protective factor for oncologic outcomes (8–10). In particular, the observation that chemerin is essential for ccRCC viability suggests that other factors, including possibly the dosage of chemerin itself, may mediate the effects chemerin has on ccRCC tumors. Altogether, these findings have potentially significant implications for diagnostics and therapy and nominate circulating adipokines as a new metabolic target for the treatment of kidney cancer.

A. Hakimi reports advisory board compensation from Merck (not related to this article or the study in any way). No disclosures were reported by the other authors.