Decoding intra-tumor heterogeneity in breast tumors towards personalized medicine.

Cellular intra-tumor heterogeneity in triple negative breast tumors (TNBC) leads to phenotypic variation between tumor subpopulations and poses a critical challenge on choosing biomarkers and therapies. We wish to decipher the complete sets of tumor cellular subclones within each tumor and the altered protein pathways that characterize those subclones in order to suggest the optimal, patient-specific, therapy. Here we propose a novel strategy, based on information theory that resolves the intra-tumor molecular heterogeneity on the single cell level and allows to break down a tumor into distinct subpopulations and the altered protein networks associated with each subpopulation. Using mice models and patient derived TNBC tumors we show that irradiation resulted in the expansion of the previously existing very small cellular groups within the tumors. We hypothesize that this expansion may lead to the resistance of TNBC to irradiation. Moreover, these results suggest that in order to sensitize certain triple negative cells to irradiation, the central proteins from the expanded subpopulations should be inhibited. We demonstrate that simultaneous targeting of central proteins representing those subpopulations, Her2 and cMet, was essential in order to sensitize TNBC to RT and stop its growth.