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


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Ariel M. Rubinstein1,Heba Alkhatib1,Swetha Vasudevan1,Shira Stefansky1,Tamar Peretz-Yablonsky2,Avital Granit2,Amichai Meirovich2,Nataly Kravchenko-Balasha1
1Hebrew University of Jerusalem,2Hadassah Medical Center

Abstract

Background

Radiation therapy (RT), which emerged more than a century ago, continues to be a key modality in the treatment and management of various types of cancer. Recent studies have shown that irradiation not only kills the cancer cells but also promotes anti-apoptotic and pro-proliferative responses. Cancer researchers search for overexpression of oncogenic druggable targets that can sensitize a tumor response to RT. However certain cancer types, such as triple negative breast cancer (TNBC), did not allow for the development of targeted strategy due to tremendous inter- and intra-tumor heterogeneity. Not a single targeted therapy has been approved for the treatment of TNBC, thus chemotherapy (CT) and radiation (RT) remain the standard TNBC treatment over the past 20 years.

Method

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, measured 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.

Results

Conclusion