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Secretome identification of immune cell factors mediating metastatic cell homing.

ABSTRACT: Metastatic cell homing is a complex process mediated in part by diffusible factors secreted from immune cells found at a pre-metastatic niche. We report on connecting secretomics and TRanscriptional Activity CEll aRray (TRACER) data to identify functional paracrine interactions between immune cells and metastatic cells as novel mediators of homing. Metastatic breast cancer mouse models were used to generate a diseased splenocyte conditioned media (D-SCM) containing immune cell secreted factors. MDA-MB-231 metastatic cell activity including cell invasion, migration, transendothelial migration, and proliferation were increased in D-SCM relative to control media. Our D-SCM secretome analysis yielded 144 secreted factor candidates that contribute to increased metastatic cell activity. The functional mediators of homing were identified using MetaCore software to determine interactions between the immune cell secretome and the TRACER-identified active transcription factors within metastatic cells. Among the 5 candidate homing factors identified, haptoglobin was selected and validated in vitro and in vivo as a key mediator of homing. Our studies demonstrate a novel systems biology approach to identify functional signaling factors associated with a cellular phenotype, which provides an enabling tool that complements large-scale protein identification provided by proteomics.

SUBMITTER: Aguado BA

PROVIDER: S-EPMC4669442 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Secretome identification of immune cell factors mediating metastatic cell homing.

Aguado Brian A BA Wu Jia J JJ Azarin Samira M SM Nanavati Dhaval D Rao Shreyas S SS Bushnell Grace G GG Medicherla Chaitanya B CB Shea Lonnie D LD

Scientific reports 20151204

Metastatic cell homing is a complex process mediated in part by diffusible factors secreted from immune cells found at a pre-metastatic niche. We report on connecting secretomics and TRanscriptional Activity CEll aRray (TRACER) data to identify functional paracrine interactions between immune cells and metastatic cells as novel mediators of homing. Metastatic breast cancer mouse models were used to generate a diseased splenocyte conditioned media (D-SCM) containing immune cell secreted factors. ...[more]

PMID: 26634905

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Project description:Drug-induced liver injury (DILI) is a leading cause of drug attrition during drug development and a common reason for drug withdrawal from the market. The poor predictability of conventional animal-based approaches necessitates the development of alternative testing approaches. A body of evidence associates DILI with the induction of stress-response genes in liver cells. Here, we set out to identify signal transduction pathways predominantly involved in the regulation of gene transcription by DILI drugs. To this end, we employed ATTAGENE's cell-based multiplexed reporter assay, the FACTORIAL transcription factor (TF), that enables quantitative assessment of the activity of multiple stress-responsive TFs in a single well of cells. Homogeneous reporter system enables quantitative functional assessment of multiple transcription factors. Nat. Methods 5, 253-260). Using this assay, we assessed TF responses of the human hepatoma cell line HepG2 to a panel of 64 drug candidates, including 23 preclinical DILI and 11 clinical DILI compounds and 30 nonhepatotoxic compounds from a diverse physicochemical property space. We have identified 16 TF families that specifically responded to DILI drugs, including nuclear factor (erythroid-derived 2)-like 2 antioxidant response element, octamer, hypoxia inducible factor 1 alpha, farnesoid-X receptor, TCF/beta-catenin, aryl hydrocarbon receptor, activator protein-1, E2F, early growth response-1, metal-response transcription factor 1, sterol regulatory element-binding protein, paired box protein, peroxisome proliferator-activated receptor, liver X receptor, interferone regulating factor, and P53, and 2 promoters that responded to multiple TFs (cytomegalovirus and direct repeat 3/vitamin D receptor). Some of TFs identified here also have previously defined role in pathogenesis of liver diseases. These data demonstrate the utility of cost-effective, animal-free, TF profiling assay for detecting DILI potential of drug candidates at early stages of drug development.

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Secretome identification of immune cell factors mediating metastatic cell homing.

Publications

Secretome identification of immune cell factors mediating metastatic cell homing.

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