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Mamrot J, Balachandran S, Steele EJ, Lindley RA
Molecular model linking Th2 polarized M2 Tumor Associated Macrophages (TAMs) with deaminase-mediated cancer progression mutation signatures
Scand J Immunol (2019) 89:e12760.
A new and diverse range of somatic mutation signatures are observed in late-stage cancers, but the underlying reasons are not fully understood. We advance a 'combinatorial association model' for deaminase binding domain (DBD) diversification to explain the generation of previously observed cancer progression associated mutation signatures. We also propose that changes in the polarization of tumor associated macrophages (TAMs) is accompanied by the expression of deaminases with a new and diverse range of DBDs, and thus accounting for the generation of new somatic mutation signatures. The mechanism proposed is molecularly reminiscent of combinatorial association of heavy (H) and light (L) protein chains following V(D)J recombination of immunoglobulin molecules (and similarly for protein chains in heterodimers alpha/beta and gamma/delta of V(D)Js of T Cell Receptors) required for pathogen antigen recognition by B-cells and T-cells respectively. We also discuss whether extracellular vesicles (EVs) emanating from tumor enhancing M2 polarized macrophages represent a likely source of the de novo deaminase DBDs. We conclude that M2 polarized macrophages extruding EVs loaded with deaminase proteins or deaminase-specific transcription/translation regulatory factors and like information may directly trigger deaminase diversification within cancer cells, and thus account for the many new somatic mutation signatures that are indicative of cancer progression. This hypothesis now has a plausible evidentiary base, and it is worth direct testing in future investigations. A long term objective would be to identify molecular biomarkers predicting cancer progression (or metastatic disease), and to support the development of new drug targets before metastatic pathways are activated. This article is protected by copyright. All rights reserved.
Publication Date: 2019-05-01.
Last updated on Saturday, August 22, 2020