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A heterodimer of hemoglobin identifies theranostic targets on brain-metastasizing melanoma cells

ABSTRACT: Innate factors such as β-defensins may exhibit anti-cancer functions, serving as a first line of defense against incipient or dormant cancer cells. In previous studies, our lab demonstrated that hemoglobin-derived factors such as the hemoglobin beta chain or an alpha/beta heterodimer of hemoglobin trigger apoptosis and necrosis in neuroblastoma and brain-metastasizing melanoma cells, respectively. In addition to its cytotoxic function, the alpha/beta hemoglobin dimer downregulated the expression of proteins such as BRD4 and IRS2, which perform essential functions in tumorigenesis and cancer progression. In the present study, we proved the concept, raised for the first time in this study, that in addition to their anti-cancer functions, innate resistance factors could serve as pathfinders to identify theranostic targets on progressing cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278118 | GEO | 2024/10/03

REPOSITORIES: GEO

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Project description:The present study deals with functional interactions of cutaneous and brain-metastasizing human melanoma cells with brain-derived molecules. In this study we employed the unique melanoma xenograft model developed by Izraely and described in Int J Cancer. 2011 Oct 25. doi: 10.1002/ijc.27324. The present study aims to determine if brain-derived soluble factors regulate malignancy-associated functions of cutaneous and brain-metastasizing melanoma cells and identify which functions are regulated by such factors. The working hypothesis of this study is that the interactions between the brain microenvironment and melanoma cells determine metastasis formation at this organ site. The aim of the study was to evaluate the contribution of such interactions to the formation of brain metastasis in nude mice xenografted with human melanoma cells. An insight into these interactions is an essential pre-requisite for the development of effective targeted therapy for melanoma brain metastasis. We assessed the effects of soluble factors present in supernatants of short-term cultures of normal mouse brain (referred here after as brain-derived soluble factors) on several characteristics linked to melanoma brain metastasis. It was found that brain-derived soluble factors affect differentially cutaneous and brain-metastasizing melanoma cells variants in-vitro. Such factors enhanced the viability of cutaneous melanoma cells but caused an S phase arrest followed by apoptosis of brain-metastasizing cells. Brain-derived soluble factors enhanced migration of melanoma cells metastasizing to the brain, but did not affect the migration of the cutaneous variants. Such factors up-regulated the expression of the chemokine receptor CCR4 in both cutaneous and brain metastasizing melanoma cells. It is not unlikely that CCR4 ligands expressed in the brain interact with the CCR4-expressing melanoma cells thereby directing them to the brain. Brain-derived soluble factors enhanced the transmigration, across human brain endothelial cells of cutaneous but not of brain metastasizing melanoma variants. This activity could promote the capacity of the cutaneous cells to metastasize to the brain. 4 Samples (arrays) were analyzed. There is 1 replicate for each variant and each treatment. We generated pairwise comparisons between cutaneous and brain metastatic variants of the same genetic background, using Partek Genomics Suite, in the three melanoma models. Genes with p≤5% and a fold-change difference of ≥2 or <-2 were selected.

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A heterodimer of hemoglobin identifies theranostic targets on brain-metastasizing melanoma cells

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