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A heterodimer of α and β hemoglobin chains functions as an innate anticancer agent

ABSTRACT: Metastatic (as well as tumor) microenvironments contain both cancer-promoting as well as cancer restraining factors. The balance between these opposing forces determines the fate of cancer cells that disseminate to secondary organ sites. In search for microenvironmental drivers or inhibitors of metastasis, we identified, in a previous study, the beta subunit of hemoglobin (HBB) as a lung-derived antimetastatic factor. In the present study, exploring mechanisms leading to melanoma brain metastasis, we discovered that brain-derived factors restrain proliferation and induce apoptosis and necrosis of brain-metastasizing melanoma cells. Employing various purification procedures, we identified a heterodimer composed of hemoglobin alpha and beta chains that performs these anti-metastatic functions. Neither the alpha nor the beta subunit alone were inhibitory. An alpha/beta chain dimer chemically purified from human hemoglobin inhibited the cell viability of primary melanomas, melanoma brain metastasis (MBM), and breast cancer cell lines. The dimer-induced DNA damage, cell cycle arrest at the SubG1 phase, apoptosis, and significant necrosis in four MBM cell lines. Proteomic analysis of dimer-treated MBM cells revealed that the dimer downregulates the expression of BRD4, GAB2, and IRS2 proteins playing crucial roles in cancer cell sustainability and progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225459 | GEO | 2023/03/08

REPOSITORIES: GEO

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Project description:Brain metastases (BrMs) are a devastating complication of solid tumors with challenging clinical management. In this study, immunogenomic and digital spatial analyses were applied to interrogate the peripheral blood and tumor specimens derived from 53 unique patients with metastatic brain tumors originating from different solid tumors including melanoma, breast cancer, lung cancer and renal cell carcinoma. In the peripheral blood, lower levels of neutrophil -lymphocytes ratio (NLR) were detected at time of craniotomy in patients with melanoma-derived brain metastasis (MBM) vs. non-melanoma- derived brain metastasis (non-MBM). Independently from the primary tumor of derivation, patients with BrMs and increased NLR levels were characterized by shorter overall survival (OS) following craniotomy. In the tumor microenvironment (TME), molecular evaluations performed on FFPEs revealed higher expression of genes and mRNA signatures identifying NK cells, CD8 cells and B cells in MBM (n=13) vs. non-MBM brain metastasis (n=41). Focusing on CD8 cells, higher infiltration of CD8+ cells were observed in patients with MBM with longer OS following craniotomy. Spatial proteomic analysis further highlighted the infiltration of CD8+ cells, antigen presenting cells- (HLA-DR+, CD11c+, B2M+), agonists of T cell activity (CD137+, CD40+) and B cells (CD20+) enriched in MBM vs non-MBM. On the contrary, an increased expression of genes associated with neuro-development, cell- cell adhesion, neutrophil enrichment together with the increased infiltrations of cells promoting neuro-differentiation (Neun+, S100+), immune regulatory functions (CD25+, CD127+), and granulocytes aggregation (CD66b+) were observed in non-MBM vs. MBM. These findings highlight that the TME of BrMs plays a pivotal role in the pathogenesis and therapeutic resistance of BrMs derived from different solid tumors. Our results also suggest that distinct neuro-immune interplay may contribute to treatment resistance in BrMs.

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A heterodimer of α and β hemoglobin chains functions as an innate anticancer agent

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