Background. Clear cell renal cell carcinoma (ccRCC) is the most common histologically defined renal cancer. However, it is not a uniform disease and includes several genetic subtypes with different prognosis. ccRCC is also characterized by distinguished metabolic reprogramming. Tobacco smoking (TS) is an established risk factor for ccRCC with unknown effects on tumor pathobiology. Methods. We investigated the landscape of ccRCCs and paired normal kidney tissues (NKTs) using integrated transcriptomic, metabolomic and metallomic approaches in a cohort of never smokers (NS) and long-term current smokers (LTS) Caucasian males. Results. All three Omics domains consistently identified a distinct metabolic subtype of ccRCCs in LTS, characterized by activation of oxidative phosphorylation (OxPhos) coupled with reprogramming of the malate-aspartate shuttle and metabolism of aspartate, glutamate, glutamine and histidine. Cadmium, copper and inorganic arsenic accumulated in LTS tumors showing redistribution among intracellular pools, including relocation of copper into the cytochrome c oxidase complex. Gene expression signature based on the LTS metabolic subtype provided prognostic stratification of The Cancer Genome Atlas (TCGA) ccRCC tumors that was independent from genomic alterations. Conclusions. The work identified the TS related metabolic subtype of ccRCC with vulnerabilities that can be exploited for precision medicine approaches targeting metabolic pathways. The results provided rationale for the development of metabolic biomarkers with diagnostic and prognostic applications using evaluation of OxPhos status. The metallomic analysis revealed the role of disrupted metal homeostasis in ccRCC highlighting the importance of studying effects of metals from e-cigarettes and environmental exposures.
722 Background: Previous large scale genomic studies have described somatic alterations that affect tumor progression. However, metabolic and immune pathway changes that occur with advancing disease stage are not well characterized. Herein, we performed transcriptomic profiling of clear-cell renal carcinoma (ccRCC) tumors across clinical stages to define these changes. Methods: TCGA Firehose Legacy cohort was used to determine differential gene expression between stage 3 ccRCCs from patients who remained disease free (S3DF) vs. those who relapsed (S3RL) within two years of nephrectomy. Single cell RNA-seq (scRNAseq) analysis was performed on primary ccRCCs from nine patients (stage 1 n=4, stage 3 n=4, metastatic n=1). Seurat V4 package and module score was used to analyze patterns of gene expression associated with tumor progression at the single cell level. Results: Transcriptomic comparison of ccRCCs from TCGA Firehose Legacy cohort revealed induction of genes encoding mitochondrial respiratory complexes and mitochondrial ribosomal proteins (MRPs) and decrease in expression of immune genes in S3RL as compared to S3DF tumors. Using a set of 23 differentially regulated mitochondrial and immune genes we established a transcriptomic signature that stratified patients into those at risk of relapse vs. not. ScRNA-seq data analysis determined increased expression of mitochondrial respiratory complexes’ gene-sets, and decreased levels of glycolytic genes and HIF targets during tumor progression from stage-I to metastatic. This was supported by spatial transcriptomics of cancer cells, which revealed clusters of cells with high mitochondrial activity and decreased MHC class I and II gene expression. Conclusions: The data support a model of progressive metabolic reprogramming from glycolysis and HIF-regulated pathways to mitochondrial respiration in parallel with diminished immune expression of antigens on cancer cells with advancing disease stage in ccRCC. Identification of targetable mitochondrial vulnerability could be a therapeutic option in patients who progress on immune checkpoint inhibitors.
MAP1LC3C (LC3C) is a member of the microtubule associated family of proteins that are essential in the formation of autophagosomes and lysosomal degradation of cargo. LC3C has tumor suppressing activity and its expression is dependent on kidney cancer tumor suppressors, such as VHL and FLCN. Recently we demonstrated that LC3C autophagy is regulated by noncannonical upstream regulatory complexes and targets for degradation postdivision midbody rings associated with cancer cells stemness. Here we show that loss of LC3C leads to peripheral positioning of the lysosomes and lysosomal exocytosis (LE) in a subset of cells. This process is independent of the autophagic activity of LC3C. Analysis of isogenic cells with low and high LE shows substantial transcriptomic reprogramming with altered expression of Zn-related genes and activity of Polycomb Repressor Complex 2 (PRC2), accompanied by a robust decrease in intracellular Zn. Metabolomic analysis revealed alterations in amino acid steady-state levels. Cells with augmented LE show tumor initiation properties and form aggressive tumors in xenograft models. Immunocytochemistry identified high levels of LAMP1 on the plasma membrane of cancer cells in human ccRCC and reduced levels of Zn, an indication that LE is a frequent event in ccRCC, potentially contributing to the loss of Zn. Overall, these data indicate that an important tumor suppressing activity of LC3C is contributing to the reprogramming of lysosomal activity and Zn metabolism with implication for epigenetic remodeling in a subpopulation of tumor propagating properties of cancer cells.
378 Background: Patients with localized or locally advanced ccRCC undergo surgical resection by partial or radical nephrectomy. Approximately 50% of tumors recur within five years after surgery. Currently the only FDA approved drug in the adjuvant setting is sunitinib. However, the absence of an overall survival benefit and the prevalence of side effects limit widespread use of sunitinib. Accurate identification of patients at high risk of recurrence would enhance targeted adjuvant therapy, while sparing low-risk patients from side effects. A single scoring system, transcriptomic signature or genomic classifier, is unlikely to accurately define prognosis. Here, we describe an integrated transcriptomic-metallomic classifier to assess the risk of relapse in localized ccRCC. Methods: We investigated the transcriptomic landscape of Caucasian male patients with stage III ccRCCs who remained disease free (S3DF) or relapsed (S3RL) within 24 months after surgery using the TCGA Firehose Legacy cohort. In a separate cohort of S3RL and S3DF ccRCCs, copper (Cu) content and molecular distribution were analyzed by size exclusion chromatography coupled to inductively coupled plasma mass spectrometry (SEC-ICP-MS). Results: Transcriptomic analysis identified that S3RL tumors were enriched for genes encoding subunits of mitochondrial electron transport chain (ETC) and mitochondrial ribosomal proteins (MRPs), an indication that mitochondrial activity may contribute to the relapse. In contrast, S3DF tumors were enrichedfor genes related to immune responses, including genes encoding members ofMHC-II, suggesting tumor control by the immune system. We established a setof 23 genes (23G) as a signature that stratified ccRCCsinto distinct groups characterized by low, intermediateand high risk of relapse after surgery. Importantly, SEC-ICP-MS analysis identified augmented distribution of Cu to the Cu cytochrome c oxidase complex (Cu-COX) in tumor mitochondria from S3RL, consistent with the prediction of increased ETC activity in the transcriptomic analysis. Conclusions: Integration of the 23G transcriptomic signature and Cu-COX complex measurements in locoregional ccRCC can serve as a prognostic biomarker for recurrence, and as a predictive classifier for novel treatments, including inhibitors of ETC for the S3RL tumors. In particular, a combination classifier using both measurements may have a stronger prognostic/predictive power as compared to either biomarker alone.
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