Mapping Cellular Subpopulations within Triple Negative Breast Tumors Provides a Tool for Cancer Sensitization to Radiotherapy

Chemotherapy and targeted drugs are used in certain cases as radiosensitizers. However there are cancer types insensitive to both targeted drugs and radiotherapy. Triple negative breast cancer (TNBC) is an aggressive type of cancer that is hard to sensitize to radiotherapy (RT) due to lack of biomarkers and intra-tumor heterogeneity.

We propose a novel concept according to which TNBC sensitization to RT can be rationally-designed based on resolution of patient-specific intra-tumor subpopulations that emerge in response to RT treatment. The computational strategy we developed resolves the intra-tumor protein expression heterogeneity, quantified by flow cytometry at the single cell level, and allows to break down a tumor into distinct subpopulations and the altered protein networks associated with each subpopulation. More specifically, a set of altered protein-protein correlation subnetworks is computed in each cell, namely cell specific signaling signature, which is used to divide the tumor mass into intra-tumor subpopulations.

Using mice models and patient derived TNBC tumors we show that two distinct subpopulations expanded in response to RT. 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. The presented strategy can be broadly applicable to clinical use.