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APOE-mediated immunometabolic reprogramming of macrophages drives lipid delivery to tumor cells in clear-cell renal cell carcinoma — a metabolic checkpoint

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is the most common and lethal subtype of kidney cancer. Extensive evidence highlights the critical role of the von Hippel-Lindau (VHL) tumor suppressor gene in the initiation and progression of ccRCC. Our previous studies demonstrated that VHL deficiency in renal tubular epithelial cells promotes activation of the endothelial vascular network and facilitates immune cell infiltration, particularly by macrophages (Ms), into the ccRCC microenvironment. These interactions between VHL-deficient renal cells and the recruited stromal components are essential for ccRCC development. In our investigation of ccRCC-associated macrophages, we observed a significant upregulation of genes related to lipid metabolism in MΦs co-cultured with VHL-deficient tubular cells. Further analysis confirmed that these tumor-associated macrophages (TAMs) actively uptake lipids, and we called them lipid-laden macrophages (LLMs). Notably, Apolipoprotein E (APOE) emerged as one of the most highly upregulated lipid-related genes. Given APOE’s established function as a lipid-binding protein involved in lipoprotein formation and lipid uptake, we hypothesize that these macrophages transfer lipid contents to VHL-deficient tubular cells, thereby promoting the lipid-rich “clear cell” phenotype characteristic of ccRCC. To further investigate this mechanism, we isolated macrophage populations with high (APOEhi. MΦs) and low (APOElo. MΦs) APOE expression, along with control macrophages (MΦCtr), from the co-culture system. We then performed mRNA sequencing to elucidate the transcriptional landscape and functional roles of LLMs in ccRCC pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301221 | GEO | 2026/05/21

REPOSITORIES: GEO

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Project description:Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFÎ± associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFÎ± in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFÎ±-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis. RNA was extracted by RNAeasy kits (Qiagen) from the RCC4 Vec and VHL-reconstituted cells which were exposed to the control full DMEM or cystine deprived DMEM media for 6 hours (three replicates in each condition).

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APOE-mediated immunometabolic reprogramming of macrophages drives lipid delivery to tumor cells in clear-cell renal cell carcinoma — a metabolic checkpoint

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