Triangular Correlation (TrC) between cancer aggressiveness, cell uptake capability and cell deformability
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA557700 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9874450.fastq.gz | Fastqsanger.gz | |||
| SRR9874441.fastq.gz | Fastqsanger.gz | |||
| SRR9874451.fastq.gz | Fastqsanger.gz | |||
| SRR9874442.fastq.gz | Fastqsanger.gz | |||
| SRR9874452.fastq.gz | Fastqsanger.gz |
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Project description:The malignancy potential is correlated with mechanical deformability of the cancer cells. Therefore, mechanical properties of individual patient cells can contribute essential knowledge in cancer diagnostics and in precision therapies. However, clinical applications are limited by lack of current knowledge and of reliable and robust cell mechanical tests. In a comprehensive study, we found a Triangular Correlation (TrC) between cell deformability, phagocytic like capacity, and cancer aggressiveness. A significant application of the TrC is that phagocytic measurements can be a surrogate marker for detecting malignancy of cancer cells based on mechanical properties. We found that the uptake of inert sub-micron and micro-beads was massively higher in cancer cells compared with non-cancerous cells. Moreover, cells with a higher malignancy potential had greater uptake capacity. Importantly, in a reciprocal approach, we sorted either human bladder cancer cells or melanoma cells into subpopulations, solely based on their phagocytic capacity. The more phagocytic subpopulations showed elevated phenotypes of cancer aggressiveness ex vivo and in vivo. The uptake potential was found to be an imprinted feature preserved genetically and enriched over the sorting cycles. A gene expression profile revealed differences in gene sets associated with regulation of cell-cell and extracellular matrix adhesions and epithelial-to-mesenchymal transition. Chromatin immunoprecipitation sequencing showed that differences in gene expression were reflected also at the chromatin level. Importantly, in all cases studied here, enhanced phagocytic ability and elevated aggressiveness phenotypes were correlated with greater cell deformability, providing the mechanical link of the TrC. A computational model supported the notion that the uptake capacity can be a marker for malignancy mediated by cell mechanics. Our multidisciplinary approach, which involved complementary directions of study in several types of cancer cells, provides the proof of concept that phagocytic measurements can be applied for cancer diagnostics and precision medicine.
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Project description:The malignancy potential is correlated with the mechanical deformability of the cancer cells. However, mechanical tests for clinical applications are limited. We present here a Triangular Correlation (TrC) between cell deformability, phagocytic capacity, and cancer aggressiveness, suggesting that phagocytic measurements can be a mechanical surrogate marker of malignancy. The TrC was proved in human prostate cancer cells with different malignancy potential, and in human bladder cancer and melanoma cells that were sorted into subpopulations based solely on their phagocytic capacity. The more phagocytic subpopulations showed elevated aggressiveness ex vivo and in vivo. The uptake potential was preserved, and differences in gene expression and in epigenetic signature were detected. In all cases, enhanced phagocytic and aggressiveness phenotypes were correlated with greater cell deformability and predicted by a computational model. Our multidisciplinary study provides the proof of concept that phagocytic measurements can be applied for cancer diagnostics and precision medicine.
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Project description:Purpose. Aggressiveness is a crucial issue related to cutaneous melanoma malignancy and its high metastatic potential. Aim of this work is to identify new pathways or molecules controlling melanoma cell aggressiveness. Proliferation, migration and invasion capability under serum stimulation were analyzed in 12 human metastatic melanoma cell lines to identify the most aggressive ones as a model. The most proliferating/invading (defines as the most aggressive) A375 cell line was compared to the less aggressive one, Sk mel 28 by means of different approaches: 1) transcriptomic analysis by ILLUMINA platform; 2) proteomic study through LC-MS/MS analysis; 3) multiplexed assay to measure secretion of cytokines in conditioned media bioinformatic analysis was then carried out. Two groups of cells significantly differing in aggressiveness were identified and 2 cell lines, namely A375 and SK-Mel-28 were selected as model of the most and the less aggressive phenotype, respectively. A multi-omic analysis of several experimental datasets derived from transcriptomic, proteomic (mass spectrometric) and cytokinomic data was then carried out via Ingenuity Pathway Analysis (IPA) software. Analysis of upstream regulators and network analysis, indicated that the expression of tumor necrosis factor (TNF) were significantly differently expressed and functioning. The involvement of these pathways was confirmed by functional validation studies as zymography and proliferation studies and the most significantly upregulated pathway (TNF-alfa) was tested. Five melanoma cell lines with different MAGS were treated with an anti-TNFα monoclonal antibody and the most aggressive ones were highly significantly affected.
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