Abstract A33: Physical intimacy of breast cancer cells with mesenchymal stem cells elicits trastuzumab resistance through Src activation
Authors: Kidambi Srivatsan 
Published: October 2016

The development of resistance to trastuzumab is a major obstacle for lasting effective treatment of patients with ErbB2-overexpressing tumors. Here, we demonstrate that the physical contact of breast cancer cells with mesenchymal stem cells (MSCs) is a potential modulator of trastuzumab response by activation of nonreceptor tyrosine kinase c-SRC (Src) and down regulation of phosphatase and tensin homolog (PTEN). In this study we demonstrate a method for controlling breast cancer cells adhesion on polyelectrolyte multilayer (PEM) films without the aid of adhesive proteins/ligands to study the role of tumor and stromal cell interaction on cancer biology. Numerous studies have explored engineering co-culture of tumor and stromal cells predominantly using transwell co-culture of stromal cells cultured onto cover slips that were subsequently added to tumor cell cultures. However, these systems imposed an artificial boundary that precluded cell-cell interactions. To our knowledge this is the first demonstration of patterned co-culture of tumor cells and stromal cells that captures the temporal changes in the miRNA signature as the breast tumor develops through various stages. In this study we utilized cancer cells derived from two different tumor stages and two different stromal cells to effectively model heterogeneous tumor microenvironment and emulate various tumor stages. The co-culture model mimics the proliferative index (Ki67 expression) and tumor aggressiveness (HER-2 expression) akin to those observed in clinical tumor samples. We also demonstrated that our patterned co-culture model captures the temporal changes in the miRNA-21 and miRNA-34 signature as the breast tumor develops through various stages. Using our patterned breast cancer/MSC co-culture model, we find that the presence of MSCs results in Src activation that is missing in cancer cells monoculture, transwell co-culture, and cells treated with MSCs conditioned media. Interestingly, the co-culture model also results in PTEN loss and activation of PI3K/AKT pathway that has been demonstrated as fundamental proliferative and survival pathways in clinical settings. In addition, breast cancer cells in co-culture with MSCs conferred trastuzumab resistance in vitro as observed in the lack of inhibition of proliferative and migrative properties of the cancer cells. Our findings show that MSCs are potent mediators of resistance to trastuzumab and might reveal targets to enhance trastuzumab efficacy in patients. The engineered co-culture platform lays groundwork towards precision medicine wherein patient-derived tumor cells can be incorporated within our in vitro models to identify potential pathways and drug treatment regimens for individual patients.

Citation Format: Srivatsan Kidambi. Physical intimacy of breast cancer cells with mesenchymal stem cells elicits trastuzumab resistance through Src activation. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A33.