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Research Interests:Cancers are complex and dynamic entities, which evolve in tissue/organ contexts conferring a selective advantage to the malignant cells. In addition to intrinsic genetic defects and epigenetic factors, cancer cells are exposed to, and benefit from, cell non-autonomous signals that impact on critical functions, namely cell survival, latency, proliferation, metabolism, migration, morphogenesis and susceptibility to noxious agents. Also, malignant cells can and do modify their surroundings, sculpting tumor-permissive microenvironments. However, the present knowledge on the role and criticality of microenvironmental cues and host factors on cancer etiology and biology is very limited. It is our contention that the understanding of the cellular and molecular mechanisms involved in the reciprocal interactions between tumor cells and their microenvironment is essential for the development of more effective and specific therapeutic strategies. Our research aims at dissecting the mechanisms and molecular events critically implicated in the crosstalk between malignant cells and their microenvironment in the bone marrow (BM). In particular, we have been interested in BM endothelium as an important player in the tumor/microenvironment crosstalk. As models, we have been studying acute lymphoblastic leukemia, as a malignancy originated in the BM, and metastatic breast cancer, as a malignancy that frequently evolves with BM invasion. We have identified juxtacrine and paracrine factors, molecular cell-to-cell communication signals and intracellular signaling pathways that mediate the crosstalk between BM endothelial cells and tumor cells. These studies help to explain how tumor cells can recruit, modulate and "shape" the BM endothelium and, reciprocally, which beneficial signals malignant cells receive from BM endothelial cells. Importantly, our work has led to the identification and pre-clinical validation of putative targets for therapeutic intervention. The focus of our present research is directed at: 1) defining the mechanisms implicated in the transcriptional regulation of the reciprocal interactions between cancer cells and BM endothelium; 2) performing in vivo studies to define the impact of disrupting tumor-endothelium crosstalk in the development and progression of tumors in the BM, and to test strategies combining agents that specifically block distinct signaling pathways; 3) defining the signaling and transcriptional cascades implicated in the survival, maintenance and self-renewal of tumor progenitor/stem cells and on their crosstalk with tumor-supporting endothelial niches in the BM, and; 4) developing experimental models that more accurately recapitulate the architecture and complexity of BM tumors as organ/tissue systems, and that account for the biomechanical, metabolic and gaseous stimuli at which these "malignant tissues" are exposed.
Education and Training:Ph.D.: University of Paris XI Medical School, Paris, FranceFellowship: University Connecticut Medical School, Farmington, CT Fellowship: Curry Cabral Hospital, Lisbon, Portugal M.D.: Abel Salazar Institute for the Biomedical Sciences Porto University, Porto, Portugal
Recent Publications:PubMed listings |
