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Analysis of Gene Expression Heterogeneity Reveals Therapeutic Targets and Novel Regulators of Metastasis

ABSTRACT: Tumor cell heterogeneity has been implicated in metastatic progression of solid tumors such as triple-negative breast cancer (TNBC), leading to resistance and recurrence. We hypothesize that genes with low cell-to-cell transcriptional variability may be effective therapeutic targets, and that analysis of variability may facilitate identification of new metastatic regulators. Here we demonstrate, using single cell RNA sequencing, that the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP) reduced overall transcriptional variability in TNBC xenograft tumors. Focusing on genes with reduced variability in response to RKIP, we identified targetable gene sets such as oxidative phosphorylation and showed that metformin could inhibit RKIP-expressing but not control tumor growth. We also found many regulators of cancer progression including a novel epigenetic metastasis suppressor, KMT5C. These studies demonstrate that a metastatic regulator can alter transcriptional variability in tumors and reveal the importance of genes involved in heterogeneity as potential therapeutic targets and regulators of metastatic progression in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220671 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:In order to address the progression, metastasis, and clinical heterogeneity of renal cell cancer (RCC), transcriptional profiling with oligonucleotide microarrays (22,283 genes) was done on 49 RCC tumors, 20 non-RCC renal tumors, and 23 normal kidney samples. Samples were clustered based on gene expression profiles and specific gene sets for each renal tumor type were identified. Gene expression was correlated to disease progression and a metastasis gene signature was derived. Gene signatures were identified for each tumor type with 100% accuracy. Differentially expressed genes during early tumor formation and tumor progression to metastatic RCC were found. Subsets of these genes code for secreted proteins and membrane receptors and are both potential therapeutic or diagnostic targets. A gene pattern ("metastatic signature") derived from primary tumors was very accurate in classifying tumors with and without metastases at the time of surgery. A previously described "global" metastatic signature derived by another group from various non-RCC tumors was validated in RCC. Unlike previous studies, we describe highly accurate and externally validated gene signatures for RCC subtypes and other renal tumors. Interestingly, the gene expression of primary tumors provides us information about the metastatic status in the respective patients and has the potential, if prospectively validated, to enrich the armamentarium of diagnostic tests in RCC. We validated in RCC, for the first time, a previously described metastatic signature and further showed the feasibility of applying a gene signature across different microarray platforms. Transcriptional profiling allows a better appreciation of the molecular and clinical heterogeneity in RCC. We used the following tissue samples to obtain transcriptional profiling of kidney tumors using Affymetrix HGU-133A chips: 23 Normal, 32 clear cell RCC (cRCC), 11 papillary RCC (pRCC), 6 chromophobe RCC (chrRCC), 12 Oncocytoma (OC), and 8 transitional cell carcinoma (TCC). The supplementary file 'GSE15641_mas5_data.txt' contains MAS5 signal values for the Samples included in Series GSE15641. This dataset is part of the TransQST collection.

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Analysis of Gene Expression Heterogeneity Reveals Therapeutic Targets and Novel Regulators of Metastasis

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