Left-Right Asymmetry in the Breast TME is Associated with Distinct Bioelectric and Epigenetic Tumor Features

Here, we report a left-right (L-R) asymmetry in the breast TMEs. Bioinformatic analyses of RNASeq data and histological data from TCGA, revealed that R-sided tumors exhibit higher stromal content and are enriched in cancer-associated fibroblasts (CAFs).

These differences were validated in paired L-R PDX and xenograft models, where R-tumors showed increased α-SMA and PDGFRα expression. Associated with laterality, we observed an asymmetry in tumor bioelectric properties: in both PDX and xenograft models, as well as in cells cultured with L-R conditioned media, L-sided tumors consistently displayed a depolarized membrane potential relative to their R counterparts. In-vitro, these features were shown to be epigenetically regulated - abolished by the DNA methyltransferase inhibitor decitabine - and reversible upon inversion of the conditioned media laterality.