Transcriptomics,Genomics

Dataset Information

29

Transcriptomic, (phospho)proteomic, and metabolomic analysis of tumor-comprising cells treated by photodynamic therapy [mouse]


ABSTRACT: Photodynamic therapy (PDT) is a tumor treatment strategy that relies on the production of reactive oxygen species (ROS) in the tumor following local illumination. Although PDT has shown promising results in the treatment of non-resectable perihilar cholangiocarcinoma, it is still employed palliatively. In this study, tumor-comprising cells (i.e., cancer cells, endothelial cells, macrophages) were treated with the photosensitizer zinc phthalocyanine that was encapsulated in cationic liposomes (ZPCLs). Post-PDT survival pathways were studied following sublethal (50% lethal concentration (LC50)) and supralethal (LC90) PDT using a multi-omics approach. ZPCLs did not exhibit toxicity in any of the cells as assessed by toxicogenomics. Sublethal PDT induced survival signaling in perihilar cholangiocarcinoma (SK-ChA-1) cells via mainly hypoxia-inducible factor 1 (HIF-1)-, nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-кB)-, activator protein 1 (AP-1)-, and heat shock factor (HSF)-mediated pathways. In contrast, supralethal PDT damage was associated with a dampened survival response. (Phospho)proteomic and metabolomic analysis showed that PDT-subjected SK-ChA-1 cells downregulated proteins associated with epidermal growth factor receptor (EGFR) signaling, particularly at LC50. PDT also affected various components of glycolysis and the tricarboxylic acid cycle as well as metabolites involved in redox signaling. In conclusion, sublethal PDT activates multiple pathways in tumor parenchymal and non-parenchymal cells that, in tumor cells, transcriptionally regulate cell survival, proliferation, energy metabolism, detoxification, inflammation/angiogenesis, and metastasis. Accordingly, sublethally afflicted tumor cells are a major therapeutic culprit. Our multi-omics analysis unveiled multiple druggable targets for pharmacological intervention. Overall design: RAW 264.7 murine macrophages as a model for tumor-resident macrophages were analyzed by whole genome expression analysis following photodynamic therapy (PDT). Cells were incubated with buffer (control group) or received a sublethal (vehicle group, 50% lethal concentration (LC50) group) or superlethal concentration (LC90 group) of zinc phthalocyanine (ZnPC)-encapsulating cationic liposomes (ZPCLs). After 60 minutes, cells were either maintained in the dark (control group, vehicle (dark toxicity (DT)) group) or were treated with 500-mW laser light (LC50 and LC90 groups) using a cumulative light dose of 15 J/cm2 (n = 3 per group). Ninety minutes after photodynamic therapy, total cellular RNA was isolated and gene expression levels were analyzed by using the Illumina WG-6 v2.0 platform. The data was analyzed in the context of survival signalling and comparisons were made with the control group.

INSTRUMENT(S): Illumina MouseWG-6 v2.0 expression beadchip

SUBMITTER: Perry D Moerland  

PROVIDER: GSE84757 | GEO | 2016-11-25

SECONDARY ACCESSION(S): PRJNA331050

REPOSITORIES: GEO

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Publications

Multi-OMIC profiling of survival and metabolic signaling networks in cells subjected to photodynamic therapy.

Weijer Ruud R   Clavier Séverine S   Zaal Esther A EA   Pijls Maud M E MM   van Kooten Robert T RT   Vermaas Klaas K   Leen René R   Jongejan Aldo A   Moerland Perry D PD   van Kampen Antoine H C AH   van Kuilenburg André B P AB   Berkers Celia R CR   Lemeer Simone S   Heger Michal M  

Cellular and molecular life sciences : CMLS 20161101 6


Photodynamic therapy (PDT) is an established palliative treatment for perihilar cholangiocarcinoma that is clinically promising. However, tumors tend to regrow after PDT, which may result from the PDT-induced activation of survival pathways in sublethally afflicted tumor cells. In this study, tumor-comprising cells (i.e., vascular endothelial cells, macrophages, perihilar cholangiocarcinoma cells, and EGFR-overexpressing epidermoid cancer cells) were treated with the photosensitizer zinc phthalo  ...[more]

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