The Cancer Heterogeneity Lab seeks to understand tumor heterogeneity and use this knowledge to deliver new approaches to treatment of patients. Breast cancer is a particularly heterogeneous disease. The identification and characterization of cells with stem-like properties (cancer stem/progenitor cells, CSCs) in breast cancer has opened new possibilities for anti-cancer therapies. Furthermore, CSCs have been implicated in tumor initiation and resistance to current treatments, including hormone therapy. In addition, characterization of the regulation of normal epithelial cell differentiation is fundamental to understanding breast cancer heterogeneity.
A major objective of the laboratory is to gain further insight into the roles of steroid hormone receptors in normal breast tissue and during breast cancer development. Thus, the influences of hormones, other signaling factors and the microenvironment on breast stem cells and on their transformation into cancer initiating cells are being explored, particularly focusing on their effects during development of resistance to hormone therapy. Recent work from the lab has revealed the role of CSCs in resistance to tamoxifen and has highlighted the molecular heterogeneity observed in response to the cell environment. Presently, studies are in progress to improve further our knowledge of the molecular mechanisms regulating stem and cancer stem cells with the final aims of (1) identifying biomarkers of resistance to therapy and (2) progressing our understanding of breast cancer biology. Recent studies have focused on the transcription factors SOX2 and SOX9, which play key roles in CSCs in many tumor types.
The group also maintains a strong interest in secreted factors whose expression is altered in metastatic and treatment-resistant disease, such as Wnt-11, which is found upregulated in prostate and colorectal cancers. We identified FZD8 as a major Wnt-11 receptor in prostate cancer that integrates Wnt and TGF-beta signals and we have developed Wnt-11 function-blocking antibody nanoparticles, in collaboration with A. Cortajarena at CIC biomaGUNE. In addition, we study Dkk-3, which regulates the tumor microenvironment. We have identified Dkk-3 effectors and are using epigenetic approaches to restore Dkk-3 levels expression in cancer, in collaboration with colleagues at Imperial College London.