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3 results on '"Vanesa C. Sanchez"'

1. Crosstalk between tumour and stroma modifies CLIC4 cargo in extracellular vesicles

Author

Vanesa C. Sanchez, Alayna Craig‐Lucas, Christophe Cataisson, Brandi L. Carofino, and Stuart H. Yuspa

Subjects
breast cancer, CLIC4, exosomes, tumour‐stromal interaction, Cytology, QH573-671
Abstract

Abstract Mouse models of breast cancer have revealed that tumour‐bearing hosts must express the oxidoreductase CLIC4 to develop lung metastases. In the absence of host CLIC4, primary tumours grow but the lung premetastatic niche is defective for metastatic seeding. Primary breast cancer cells release EVs that incorporate CLIC4 as cargo and circulate in plasma of wildtype tumour‐bearing hosts. CLIC4‐deficient breast cancer cells also form tumours in wildtype hosts and release EVs in plasma, but these EVs lack CLIC4, suggesting that the tumour is the source of the plasma‐derived EVs that carry CLIC4 as cargo. Paradoxically, circulating EVs are also devoid of CLIC4 when CLIC4‐expressing primary tumours are grown in CLIC4 knockout hosts. Thus, the incorporation of CLIC4 (and perhaps other factors) as EV cargo released from tumours involve specific signals from the surrounding stroma determined by its genetic composition. Since CLIC4 is also detected in circulating EVs from human breast cancer patients, future studies will address its association with disease.

Published
2023
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2. The oxidoreductase CLIC4 is required to maintain mitochondrial function and resistance to exogenous oxidants in breast cancer cells

Author

Heba Al Khamici, Vanesa C. Sanchez, Hualong Yan, Christophe Cataisson, Aleksandra M. Michalowski, Howard H. Yang, Luowei Li, Maxwell P. Lee, Jing Huang, and Stuart H. Yuspa

Subjects
Apoptosis, Breast Neoplasms, Cell Biology, Hydrogen Peroxide, Biochemistry, Mitochondria, Mitochondrial Proteins, Mice, Necrosis, Proto-Oncogene Proteins c-bcl-2, Chloride Channels, Superoxides, Cell Line, Tumor, Animals, Female, RNA, Messenger, Molecular Biology, Gene Deletion, Glutaredoxins
Abstract

The chloride intracellular channel-4 (CLIC4) is one of the six highly conserved proteins in the CLIC family that share high structural homology with GST-omega in the GST superfamily. While CLIC4 is a multifunctional protein that resides in multiple cellular compartments, the discovery of its enzymatic glutaredoxin-like activity in vitro suggested that it could function as an antioxidant. Here, we found that deleting CLIC4 from murine 6DT1 breast tumor cells using CRISPR enhanced the accumulation of reactive oxygen species (ROS) and sensitized cells to apoptosis in response to H

Published
2022

3. Host CLIC4 expression in the tumor microenvironment is essential for breast cancer metastatic competence

Author

Vanesa C. Sanchez, Howard H. Yang, Alayna Craig-Lucas, Wendy Dubois, Brandi L. Carofino, Justin Lack, Jennifer E. Dwyer, R. Mark Simpson, Christophe Cataisson, Max P. Lee, Ji Luo, Kent W. Hunter, and Stuart H. Yuspa

Subjects
Proteomics, Cancer Research, Breast Neoplasms, Mice, Chloride Channels, Transforming Growth Factor beta, Genetics, Tumor Microenvironment, Animals, Humans, Female, Neoplasm Metastasis, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics
Abstract

The TGF-β-regulated Chloride Intracellular Channel 4 (CLIC4) is an essential participant in the formation of breast cancer stroma. Here, we used data available from the TCGA and METABRIC datasets to show that CLIC4 expression was higher in breast cancers from younger women and those with early-stage metastatic disease. Elevated CLIC4 predicted poor outcome in breast cancer patients and was linked to the TGF-β pathway. However, these associations did not reveal the underlying biological contribution of CLIC4 to breast cancer progression. Constitutive ablation of host Clic4 in two murine metastatic breast cancer models nearly eliminated lung metastases without reducing primary tumor weight, while tumor cells ablated of Clic4 retained metastatic capability in wildtype hosts. Thus, CLIC4 was required for host metastatic competence. Pre- and post-metastatic proteomic analysis identified circulating pro-metastatic soluble factors that differed in tumor-bearing CLIC4-deficient and wildtype hosts. Vascular abnormalities and necrosis increased in primary tumors from CLIC4-deficient hosts. Transcriptional profiles of both primary tumors and pre-metastatic lungs of tumor-bearing CLIC4-deficient hosts were consistent with a microenvironment where inflammatory pathways were elevated. Altogether, CLIC4 expression in human breast cancers may serve as a prognostic biomarker; therapeutic targeting of CLIC4 could reduce primary tumor viability and host metastatic competence.

Published
2022

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