Growth factor signaling in the breast tumor microenvironment

Abstract: Cancer represents a collection of malignancies characterized by an aberrant expansion of cells. This unrestrained growth is the result of the acquisition of several pro-survival features and the evasion of cellular fail-safe mechanisms, collectively known as the hallmarks of cancer. In the clinical setting, disease management has heavily relied on the sole targeting of malignant cells but, except for rare cases, monotherapy regimens showed insufficient antitumor activity. Indeed, translational and clinical studies revealed that cancer cells almost invariably adapt to treatment, mainly through acquisition of additional (epi)mutations and/or clonal diversification and activation of bypass signaling pathways. In parallel, characterization of the malignant mass exposed the existence of other (non- transformed) cell types and non-cellular constituents, with specialized functions and potentially different origins, jointly reffered to as the tumor stroma. This local microenvironment is educated by and coevolves with the cancer cells by engaging in an intricate network of communication that plays a fundamental role in the establishment, progression and malignization of a tumor, as well as modulating the response to treatment. The stroma comprises the endothelial cells and pericytes that compose the vasculature, fibroblasts, immune cells and the extracellular matrix. Therefore, the genetic make-up of polyclonal tumors and the composition of the microenvironment define the genomic, spatial and functional diversity of each tumor, also at the metastatic site. In agreement with this, the concept of intratumoral heterogeneity denotes a key aspect that has been increasingly recognized, although not fully implemented, in personalized medicine. Moreover, recent efforts have started to address the systemic changes instigated by the tumor mass –including metabolism– and how these influence the survival/dormancy, the colonization and the metastatic growth of disseminated cancer cells.In the papers included in this thesis, we made use of experimental breast cancer models to deepen our understanding of the tumor milieu and its clinical implications. Paper I reports the results of the preclinical trials of a compound that was designed to block activin receptor-like kinase (ALK)1, a protein involved in the formation of the blood vessels. Experimental models showed promising inhibition of tumor growth and marked reduction of the metastatic disease. In paper II, we analyzed how ALK1 communicates in different tumors in order to determine a set of characteristics that might help to predict which patients could benefit from ALK1-blocking therapy. Moreover, we discovered that the presence of ALK1 in tumor blood vessels influences the presence and function of the immune cells. In paper III, we define a novel therapeutic opportunity for the basal subtype of breast cancer, for which only surgery, radio- and chemotherapy are currently available. We identified the specific role of PDGF-C, that is released by tumor cells to activate fibroblasts. This communication loop maintains the tumor cells in a more aggressive state and makes them resistant to treatment. Thus, by blocking PDGF-C, tumor cells transform to a less aggressive luminal type and become sensitive to endocrine therapy, which can be used to limit the development of the tumor mass. Finally, paper IV gives us information about the diversity of the cells within the fibroblast population. By using a state of the art technology, we increased the resolution at which we are able to distinguish the function of each individual fibroblast isolated from a tissue, and match it with a specific cell-of-origin.Taken together, the use of mouse models of cancer allows us to reproduce the complexity of human tumors, and delineate how these cellular relationships are shaped and maintained during tumor development. Our data illustrate the value of impinging on the crosstalk between tumor cells and other components of the tumor mass to develop novel therapeutic strategies for the clinical management of breast cancer.