Project 3
" Impact of the microenvironment therapeutic response"
Principal Investigators: Mary Helen Barcellos-Hoff, Mina Bissell
LBNL, Life Sciences Division
Breast cancer evolves in a dynamic microenvironment. The epithelial cancer cells subvert and recruit other host cells as the cancer progresses to the invasive stage. In turn, fibroblasts, myoepithelial cells and the endothelium act upon the cancer cells themselves. We now know that extracellular matrix (ECM) and growth factors can radically alter the behavior of cancer cells1, and that context can strongly influence how cancer cells respond to therapeutic agents2. In the tumor context, the extracellular matrix is both a product of the breast cancer cells and the host cells, and that variation in the tumor cell genome and transcriptome modulate this response. We hypothesize that the response of breast cancer to therapeutic agents is modified by this complex microenvironment.
We predict that the cellular composition of the microenvironment is crucial for predicting which agents will successfully control each given breast cancer. We also believe that the failure to consider the role of the microenvironment may partially account for our failure to successfully treat some breast cancers. We therefore posit that it is important to test new therapeutics considering the context of normal tissue and the particular malignant tumor.
Further, we postulate that the therapy in turn will modify both the cancer cells and the microenvironment. We have shown for example that ionizing radiation, widely used in breast cancer therapy, persistently alters both the composition of the stroma in mice3 and cell-cell and cell-ECM interaction in human breast epithelial cells in three-dimensional cultures (3D)4. As a result of fractionated therapy, treated tumor tissue is the norm at the start of therapy. It is thus important to be mindful of the fact that the phenotype of the tumors is constantly changing as a function of the stage and duration, as well as modality of therapy.
Our objective is to critically examine the influence of microenvironmental interactions (i.e. cell-ECM, cell-cell- myoepithelial and stromal- interactions) on therapeutic responses and to use this information to increase the accuracy with which we can model the signaling pathways both experimentally and computationally. We will accomplish this by studying representative subclasses of the 60 breast cancer cell lines that comprise the “system” that is the overall focus of this Integrative Cancer Biology Project.