Pluto Bioinformatics

GSE141057: CLIC4 is essential for host competence for metastasis in murine models of breast cancer and a prognostic indicator for human breast cancer

Bulk RNA sequencing

CLIC4 belongs to a family of highly conserved metamorphic proteins of the glutathioneStransferase superfamily and dysregulation is implicated in pulmonary arterial hypertension, asthma, and ovarian cancer. We show that genetic ablation of host Clic4 eliminated the establishment of breast cancer lung metastases in two independent mouse models while Clic4 null tumor cells retained metastatic capability. TCGA and METABRIC data indicated that CLIC4 is elevated in human breast cancers from young women, those with poor prognosis and those with early stage metastatic disease. Experimentally, the essential Clic4 host contributions for metastatic competence depended on circulating levels of pro metastatic mediators, neoangiogenesis, tumor cell attachment to lung tissue, myofibroblast differentiation, and leukocyte migration. CLIC4 was abundant in circulating extracellular vesicles (EVs) from tumorbearing wildtype mice but absent in EVs from tumorbearing Clic4 null hosts or wildtype hosts bearing Clic4 nulltumors suggesting crosstalk between host and tumor cells is required to deposit CLIC4 in EVs. These results illuminate CLIC4 as a critical host factor for metastatic competence, a potential prognostic marker for breast cancer patients and a target for antimetastatic therapy. SOURCE: Helene Rosenberg (hrosenberg@niaid.nih.gov) - Inflammation Immunobiology Section National Institutes of Health