The melanoma brain metastatic microenvironment: aldolase C partakes in shaping the malignant phenotype of melanoma cells – a case of inter‐tumor heterogeneity

Izraely, Sivan; Ben-Menachem, Shlomit; Sagi‐Assif, Orit; Meshel, Tsipi; Malka, Sapir; Telerman, Alona; Bustos, Matías A.; Ramos, Romela Irene; Pasmanik‐Chor, Metsada; Hoon, Dave S.B.

doi:10.1002/1878-0261.12872

Cited by 14 publications

(16 citation statements)

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“…This intertumor heterogeneity poses a significant challenge in the clinic as the response to therapy may vary significantly among patients 53 . Previous studies from our lab indicated a significant molecular and functional intertumor heterogeneity among the melanoma cell lines used 17,54‐56 . In contrast to this heterogeneity, all four cell lines employed in the present study underwent cell cycle arrest and cell death after exposure to the Hgb dimer.…”

Section: Discussionmentioning

confidence: 61%

“…53 Previous studies from our lab indicated a significant molecular and functional intertumor heterogeneity among the melanoma cell lines used. 17,[54][55][56] In contrast to this heterogeneity, all four cell lines employed in the present study underwent cell cycle arrest and cell death after exposure to the Hgb dimer. This supports the conclusion that the Hgb dimer can be considered a general inhibitor of melanoma and perhaps other brain-metastasizing cells.…”

Section: Discussionmentioning

confidence: 81%

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

Chelladurai,

Xu,

Izraely

et al. 2023

Intl Journal of Cancer

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Metastatic (as well as tumor) microenvironments contain both cancer‐promoting and 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 regulating 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 perform these antimetastatic functions. Neither the alpha nor the beta subunit alone was 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. Thus, we hypothesize that the hemoglobin dimer functions as a resistance factor against brain‐metastasizing cancer cells.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 81%

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

Chelladurai,

Xu,

Izraely

et al. 2023

Intl Journal of Cancer

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“… 17 , 18 Specifically, TRPM1, enolase, and aldolase have been closely associated with melanoma. 19 , 20 , 21 Funduscopic changes of AIR are characteristically unremarkable at presentation but have been documented to change over time and include vascular attenuation, diffuse chorioretinal atrophy, and retinal pigment epithelium mottling. 22 Full-field ERG of our patient demonstrated attenuated a- and b-waves more consistent with CAR and cases of non-paraneoplastic AIR rather than MAR which classically exhibit electronegative b-waves.…”

Section: Discussionmentioning

confidence: 99%

Pigmentary retinopathy associated with immune therapy for advanced cutaneous melanoma

Lin¹,

Park²,

Daniels³

et al. 2023

American Journal of Ophthalmology Case Reports

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“…ALDOC was identified as activators of Wnt signaling, a signaling pathway involved in cancer genesis and progression when it was over-activated ( Caspi et al, 2014 ). Meanwhile, ALDOC was overexpressed in gallbladder carcinoma ( Fan et al, 2020 ), melanoma ( Izraely et al, 2020 ), and lung cancer ( Yuan et al, 2021 ), associated with their growth or pathogenesis. BATF3 is an AP-1 family transcription factor that controls the differentiation of CD8(+) thymic conventional dendritic cells in the immune system.…”

Section: Discussionmentioning

confidence: 99%

Establishment of Prognosis Model in Acute Myeloid Leukemia Based on Hypoxia Microenvironment, and Exploration of Hypoxia-Related Mechanisms

Zhong

et al. 2021

Front. Genet.

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Acute myeloid leukemia (AML) is a highly heterogeneous hematologic neoplasm with poor survival outcomes. However, the routine clinical features are not sufficient to accurately predict the prognosis of AML. The expression of hypoxia-related genes was associated with survival outcomes of a variety of hematologic and lymphoid neoplasms. We established an 18-gene signature-based hypoxia-related prognosis model (HPM) and a complex model that consisted of the HPM and clinical risk factors using machine learning methods. Both two models were able to effectively predict the survival of AML patients, which might contribute to improving risk classification. Differentially expressed genes analysis, Gene Ontology (GO) categories, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to reveal the underlying functions and pathways implicated in AML development. To explore hypoxia-related changes in the bone marrow immune microenvironment, we used CIBERSORT to calculate and compare the proportion of 22 immune cells between the two groups with high and low hypoxia-risk scores. Enrichment analysis and immune cell composition analysis indicated that the biological processes and molecular functions of drug metabolism, angiogenesis, and immune cell infiltration of bone marrow play a role in the occurrence and development of AML, which might help us to evaluate several hypoxia-related metabolic and immune targets for AML therapy.

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The melanoma brain metastatic microenvironment: aldolase C partakes in shaping the malignant phenotype of melanoma cells – a case of inter‐tumor heterogeneity

Cited by 14 publications

References 50 publications

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

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

Pigmentary retinopathy associated with immune therapy for advanced cutaneous melanoma

Establishment of Prognosis Model in Acute Myeloid Leukemia Based on Hypoxia Microenvironment, and Exploration of Hypoxia-Related Mechanisms

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