PhD Gonzalo Sanchez-Duffhues
My research over the past ten years has been focused on the mechanisms underlying unbalanced Transforming growth factor (TGF)-b signalling in human disease. Disruptions in TGF-b signalling have a major translational impact, causing a dysregulation in TGF-b, Activin and Bone morphogenetic protein (BMP) signalling. Therefore, identifying druggable targets and novel small molecules becomes key to normalize aberrant TGF-b signal transduction and contribute to finding a cure for human disorders.
Fibrodysplasia ossificans progressiva (FOP) represents a paradigmatic disease to investigate TGF-b signalling. FOP patients develop a so-called secondary skeleton in response to inflammatory episodes or flare-ups. FOP has been linked with heterozygous gene point mutations in ACVR1, encoding the BMP type I receptor ALK2. The mutant ALK2 receptor provokes aberrant responses to ligands of the TGF-b superfamily, eventually enhancing the differentiation capacity of bone progenitor cells. Using FOP patient-derived cell models in combination with complex 3D in vitro platforms and -omics approaches, we aim to identify potential therapeutic targets and/or biomarkers for FOP, as well as other conditions characterized by aberrant BMP signalling and low and high mass bone disorders.
Mutations in TGF-b signalling components constitute a hallmark in fibrotic and cardiovascular diseases (CVD). TGF-b-regulated endothelial-mesenchymal transition (EndMT) is an extreme form of cell plasticity by which endothelial cells can become multipotent stem-like cells, and eventually myofibroblasts, adipocytes or osteo/chondrogenic cells. The relevance of this process in tissue engineering applications and CVD onset and development is only growing in the last decade. We apply advanced in vitro and in vivo models to study specific cellular factors regulating EndMT with potential as therapeutic targets and biomarkers. We believe that achieving a precise control of EndMT will offer a new avenue for drug development in conditions such as Pulmonary arterial hypertension (PAH), cardiac fibrosis and atherosclerosis.
Following my education as Biochemist in the University of Cordoba (Spain), I enrolled in my PhD studies at the Department of Cell Biology, Physiology and Immunology in the same University. During this period, I investigated the signal transduction pathways activated by pro-inflammatory cytokines, and identified novel (semi)synthetic compounds with anti-inflammatory properties. While working at the group of Prof. Peter ten Dijke during my postdoctoral research, I investigated the crosstalk between inflammation and TGF-b signalling in vascular calcification and Fibrodysplasia ossificans progressiva. In 2017 I became a Senior member of the group headed by Prof. Marie-Jose Goumans, to further expand my background in TGF-b signalling and stem cell biology. During my years at the LUMC, I have obtained my own funding through competitive grant programs, personal awards and collaborations with biotech companies. I have broad supervision and teaching experience, and I am actively involved in institutional research committees and scientific associations, including patient organizations, where I disseminate our recent team developments in a lay understandable manner. Recently I have been elected as Young Academy member of the European Calcified Tissue Society, which gathers 50 of the most talented young researchers in the musculoskeletal field.
Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation
Keane Kenswil#, Paola Pisterzi#, Gonzalo Sánchez-Duffhues# et al. #Shared first authorship
Cell Stem Cell, (2021) 28(4): 653-670.
Bone morphogenetic protein receptors: structure, function and targeting by selective small molecule kinase inhibitors
Gonzalo Sanchez-Duffhues, Eleanor Williams, Marie-José Goumans, Carl-Henrik Heldin, Peter Ten Dijke
Bone, (2020). 138: 115472
Development of Macrocycle kinase inhibitors for ALK2 using Fibrodysplasia ossificans progressiva-derived endothelial cells
G. Sánchez-Duffhues, E. Williams, P. Benderitter, V. Orlova, M. van Wijhe, A. Garcia de Vinuesa, J. Caradec, H. de Boer, MJ Goumans, M. Eeckhoff, A. Morales Piga, J. Bachiller, P. Koolwijk, A. Bullock, J. Hoflack, Peter ten Dijke
JBMR Plus, (2019). 3(11): e10230