The melanoma brain metastatic microenvironment: aldolase C partakes in shaping the malignant phenotype of melanoma cells – a case of inter‐tumor heterogeneity |
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| Authors: | Sivan Izraely,Shlomit Ben‐ Menachem,Orit Sagi‐ Assif,Tsipi Meshel,Sapir Malka,Alona Telerman,Matias A. Bustos,Romela Irene Ramos,Metsada Pasmanik‐ Chor,Dave S. B. Hoon,Isaac P. Witz |
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| Affiliation: | 1. The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Science, Tel Aviv University, Israel ; 2. Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John''s Health Center, Santa Monica CA, USA ; 3. Bioinformatics Unit, The George S. Wise Faculty of Life Science, Tel Aviv University, Israel |
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| Abstract: | Previous studies indicated that microglia cells upregulate the expression of aldolase C (ALDOC) in melanoma cells. The present study using brain‐metastasizing variants from three human melanomas explores the functional role of ALDOC in the formation and maintenance of melanoma brain metastasis (MBM). ALDOC overexpression impacted differentially the malignant phenotype of these three variants. In the first variant, ALDOC overexpression promoted cell viability, adhesion to and transmigration through a layer of brain endothelial cells, and amplified brain micrometastasis formation. The cross‐talk between this MBM variant and microglia cells promoted the proliferation and migration of the latter cells. In sharp contrast, ALDOC overexpression in the second brain‐metastasizing melanoma variant reduced or did not affect the same malignancy features. In the third melanoma variant, ALDOC overexpression augmented certain characteristics of malignancy and reduced others. The analysis of biological functions and disease pathways in the ALDOC overexpressing variants clearly indicated that ALDOC induced the expression of tumor progression promoting genes in the first variant and antitumor progression properties in the second variant. Overall, these results accentuate the complex microenvironment interactions between microglia cells and MBM, and the functional impact of intertumor heterogeneity. Since intertumor heterogeneity imposes a challenge in the planning of cancer treatment, we propose to employ the functional response of tumors with an identical histology, to a particular drug or the molecular signature of this response, as a predictive indicator of response/nonresponse to this drug.Abbreviations- ALDOC
- aldolase C
- BBB
- blood–brain barrier
- BEC
- brain endothelial cells
- CM
- conditioned medium
- CNS
- central nervous system
- ECM
- extracellular matrix
- MBM
- melanoma brain metastasis
- MCM
- melanoma‐conditioned medium
- MGCM
- microglia‐conditioned medium
- MMP‐2
- matrix metalloproteinase‐2
- RS9
- ribosomal protein S9
- TEM
- transendothelial migration
- β2m
- β2 microglobulin
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| Keywords: | aldolase C brain metastasis melanoma microglia tumor microenvironment |
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